Oral drug dosage form comprising drug in the form of nanoparticles

ABSTRACT

The present disclosure provides a stable solid pharmaceutical dosage form for oral administration. The dosage form includes a substrate that forms at least one compartment and a drug content loaded into the compartment. The dosage form is so designed that the active pharmaceutical ingredient of the drug content is released in a controlled manner.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/028,305, filed Jul. 5, 2018, and Ser. No. 15/173,596, filed Jun. 3,2016, which claims priority to U.S. Provisional Patent Application Ser.Nos. 62/170,645, filed Jun. 3, 2015, 62/296,087, filed Feb. 17, 2016,and 62/313,092, filed Mar. 24, 2016, the disclosures of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention generally relates to a pharmaceutical dosage formand controlled release of biologically active agents, diagnostic agents,reagents, cosmetic agents, and agricultural/insecticide agents.

BACKGROUND

Pharmaceutical drug products must be manufactured into dosage forms inorder to be marketed for use. Conventional dosage forms typicallyinvolve a mixture of active pharmaceutical ingredients and inactivecomponents (excipients), along with other non-reusable materials such asa capsule shell. Categories of dosage forms include liquid dosage forms(e.g., solutions, syrups, elixirs, suspensions and emulsions), soliddosage forms (e.g., tablets, capsules, caplets and gel-caps), andsemi-solid dosage form (e.g., ointments and suppositories), among whichsolid dosage forms are more advantages to administer drugs in systemiceffect through oral route.

Tablets are most commonly used solid dosage forms, which shows morebenefits in terms of manufacturing, packaging and shipping, and easy toidentify and swallow. After being administered into a living organism, atablet undergoes interplay with the body in exerting pharmaceuticaleffects. The active pharmaceutical ingredient must be released from thetablet before being absorbed into the blood circulation. Thepharmaceutical ingredient then disperses, disintegrates or dissolvesthroughout the fluids and tissues of the body. During drug absorption,disposition, metabolism, and elimination process, dosage forms play acritical role in determining the release profile and bioavailability ofthe drugs. Therefore, there is a continuing needs for developing dosageforms that provides controlled drug delivery systems, which may offerdesired drug plasma levels, reduced side effects as well as improvedpatient compliance.

BRIEF SUMMARY OF THE INVENTION

In one aspect, the present disclosure provides a dosage form including asubstrate forming at least one compartment and a drug content loadedinto the compartment. In certain embodiments, the drug content isoperably linked to the substrate. In certain embodiments, the drugcontent is detached from the substrate and freely movable in thecompartment.

In certain embodiments, the substrate is made from a thermoplasticmaterial selected from the group consisting of a hydrophilic polymer, ahydrophobic polymer, a swellable polymer, a non-swellable polymer, aporous polymer, a non-porous polymer, an erodible polymer, anon-erodible polymer. In certain embodiments, the thermoplastic materialis selected from the group consisting of polyvinyl caprolactam-polyvinylacetate-polyethylene glycol graft copolymer 57/30/13,polyvinylpyrrolidone-co-vinyl-acetate (PVP-VA),polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA) 60/40,polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) andpolyvinylpyrrolidone (PVP) 80/20, polyethylene glycol-polyvinyl alcoholgraft copolymer 25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinylalcohol (PVA or PV-OH), poly(vinyl acetate) (PVAc), poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methylmethacrylate) 1:2:1, poly(dimethylaminoethylmethacrylate-co-methacrylicesters), poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride),poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1,poly(methacrylic acid-co-methylmethacrylate) 1:2, poly(methacylicacid-co-ethyl acrylate) 1:1, poly(methacylic acid-co-methylmethacrylate) 1:1, poly(ethylene oxide) (PEO), poly(ethylene glycol)(PEG), hyperbranched polyesteramide, hydroxypropyl methylcellulosephthalate, hypromellose phthalate, hydroxypropyl methylcellulose orhypromellose (HMPC), hydroxypropyl methylcellulose acetate succinate orhypromellose acetate succinate (HPMCAS), poly(lactide-co-glycolide)(PLGA), carbomer, poly(ethylene-co-vinyl acetate), ethylene-vinylacetate copolymer, polyethylene (PE), and polycaprolactone (PCL),hydroxyl propyl cellulose (HPC), Polyoxyl 40 Hydrogenerated Castor Oil,Methyl cellulose (MC), Ethyl cellulose (EC), Poloxamer, hydroxypropylmethylcellulose phthalate (HPMCP), Poloxamer, Hydrogenated Castor &Soybean Oil, Glyceryl Palmitostearate, Carnauba Wax, polylactic acid(PLA), polyglycolic acid (PGA), Cellulose acetate butyrate (CAB),Colloidal Silicon, Dioxide, Sucrose, Glucose, Polyvinyl AcetatePhthalate (PVAP) and a combination thereof.

In certain embodiments, the compartment has a shape selected from thegroup consisting of a pie shape, a cone shape, a pyramid shape, acylindrical shape, a cubic or cuboidal shape, a triangular or polygonalprism shape, a tetrahedron and a combination thereof.

In certain embodiments, the first drug content is in a form ofnanoparticles, microneedles or forms a net.

In certain embodiments, the drug content comprises an activepharmaceutical ingredient (API). In certain embodiments, the API isselected from the groups consisting of local anesthetics, antiepilepticdrugs and anticonvulsants, anti-Alzheimer's disease drugs, analgesics,antipodagric, anti-hypertensive drugs, antiarrhythmic drugs, diureticdrugs, drugs for treating liver diseases, drugs for treating pancreaticdiseases, antihistamine drugs, anti-allergic drugs, glucocorticoiddrugs, hormone drugs and contraceptive drugs, hypoglycemic drugs,anti-osteoporosis drugs, antibiotics, sulfonamides, quinolones, andother synthetic antibacterial drugs, anti-tuberculosis drugs, antiviraldrugs, anti-neoplasm drugs, immune-modulators, cosmetically activeagents and traditional Chinese medicine. In certain embodiments, the APIis a biologically active agent, a diagnostic agent, a reagent forscientific research, a cosmetic agent, or an agricultural/insecticideagent.

In certain embodiments, the drug content further comprises an excipient.In certain embodiments, the excipient is made from materials selectedfrom the group consisting of cocoa butter, polyethylene glycol (PEG),sucrose, glucose, galactose, fructose, xyloselactose, maltose,trehalose, sorbitol, mannitol, maltodextrins, raffinose, stachyose,fructo-oligosaccharides, water-soluble oligomers and polymers and acombination thereof.

In certain embodiments, the compartment has an aperture that is blockedand/or sealed by a plug. In certain embodiments, the plug is made from aporous polymer, an erodible polymer, a pH sensitive polymer or naturaloccurring material such as shellac. In certain embodiments, the plug ismade from a material selected from the group consisting of water-solublepolymers, erodible or dissolvable polymers, wax like materials orsaccharides or any materials mentioned above.

In certain embodiments, the dosage form comprises a gas-generatingcomponent loaded into the first compartment. In certain embodiments, thegas-generating component is selected from the group consisting ofwater-soluble carbonates, sulphites, bicarbonates, sodium carbonate,sodium bicarbonate, sodium metabisulphite, calcium carbonate, andcombinations thereof, which on contact with gastric fluid releasescarbon dioxide or sulphur dioxide gas. In certain embodiments, thegas-generating component is a combination of sodium bicarbonate andorganic acid (e.g., citric acid, tartaric acid etc).

In another aspect, the present disclosure provides a dosage formincluding a substrate forming at least a first compartment and a secondcompartment. The dosage form includes a first drug content loaded intothe first compartment and a second drug content loaded into the secondcompartment.

In certain embodiments, the first compartment and the second compartmentare connected. In certain embodiments, the first compartment and thesecond compartment are disconnected.

In certain embodiments, the first drug content is the same as the seconddrug content. In certain embodiments, the first drug content isdifferent from the second drug content.

In certain embodiments, the first compartment has a first aperture thatis covered by a first plug, and the second compartment has a secondaperture that is covered by a second plug. In certain embodiments, thefirst plug is more permeable than the second plug. In certainembodiments, the first plug erodes faster than the second plug.

In certain embodiments, the first compartment is enclosed by a firstwall, and the second compartment is enclosed by a second wall.

In certain embodiments, the first wall is thicker than the second wall.In certain embodiments, the first wall is more permeable than the secondwall. In certain embodiments, the first wall erodes faster than thesecond wall.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows a conventional dosage form comprising a drug content.

FIG. 1B illustrates the release profile of the dosage form of FIG. 1Awhen administered to a subject.

FIG. 1C shows the plasma drug level when the dosage form of FIG. 1A isadministered to a subject.

FIG. 1D shows the plasma drug level of a controlled release dosage formhaving the zero-order drug release profile when administered to asubject.

FIG. 2A shows an exemplary dosage form having a substrate that forms acompartment with a drug content loaded into the compartment.

FIG. 2B shows the release of the API from the dosage form illustrated inFIG. 2A.

FIG. 3 shows an exemplary dosage form having a substrate that forms acompartment with another dosage form loaded into the compartment.

FIG. 4A shows an exemplary dosage form having a substrate forming acompartment of pie shape.

FIG. 4B shows an exemplary dosage form having a substrate formingmultiple compartments containing various sized openings.

FIG. 4C shows an exemplary dosage form having a substrate forming anangled compartment.

FIG. 4D shows an exemplary dosage form having a substrate formingmultiple compartments of different sized radius.

FIG. 4E shows an exemplary dosage form having a substrate formingmultiple compartments of different geometric-shape that can be used tomodulate release rate of the API.

FIG. 5 shows the cross section of an exemplary dosage form having apie-shaped compartment.

FIG. 6 shows an exemplary dosage form having a substrate that formslayers with drug content in the form of nanoparticles dispersed betweenthe layers.

FIG. 7 shows an exemplary dosage form having a substrate that forms acompartment with a microneedle-shaped drug content loaded into thecompartment.

FIG. 8A shows an exemplary dosage form having a substrate forming acompartment loaded with a drug content. The drug content forms anetwork. The substrate is made of a material that dissolves between 1-5minutes, and the drug content dissolves in seconds.

FIG. 8B shows the quick release of the API from the dosage formillustrated in FIG. 8A.

FIG. 9 shows an exemplary dosage form having a substrate forming aplurality of column-shaped compartments. Each compartment is loaded withone drug content. The release of the drug content can be controlled bythe number and size of the compartments.

FIG. 10A shows an exemplary dosage form having a substrate forming threecolumn-shaped compartments. Each compartment is loaded with one drugcontent. Each drug content has a plug that blocks the aperture of eachcompartment.

FIG. 10B shows an exemplary dosage form having a multiple-layeredsubstrate with drug content embedded into each layer.

FIG. 10C shows the consequential release of the drug content from thedosage form illustrated in FIG. 10A or 10B.

FIG. 10D shows the plasma drug level of the controlled release dosageform illustrated in FIG. 10A or 10B when administered to a subject.

FIG. 11 is a schematic workflow for using of a three-dimensional printerfor preparing patient specific dosage form.

FIG. 12A shows an exemplary dosage form having a three-layered substratewith different drug content embedded into each layer.

FIG. 12B illustrates the release of three APIs from the dosage formillustrated in FIG. 12A.

FIG. 13A shows an exemplary dosage form having a substrate forming threecompartments, each of which loaded with one drug content. The releaseprofile of the drug content can be controlled by the dissolution rate ofthe drug content.

FIG. 13B illustrates the release profile of the APIs from the dosageform illustrated in FIG. 13A.

FIG. 14A shows an exemplary dosage form having a substrate having threepie-shaped segments, with drug content embedded into each segment.

FIG. 14B shows an exemplary dosage form having a substrate having threepie-shaped segments wrapped with a shell structure.

FIG. 14C shows the release profile of the APIs from the dosage formsillustrated in FIG. 8A and FIG. 8B.

FIG. 15A shows an exemplary dosage form having a substrate forming acompartment filled with a drug content. A second API is embedded in thesubstrate and is released when the substrate dissolves.

FIG. 15B shows the controlled release of the APIs from the dosage formillustrated in FIG. 15A.

FIG. 16A shows an exemplary dosage form having a substrate forming threecolumn-shaped compartments. Each compartment is loaded with one drugcontent. Each drug content has a plug that blocks the opening of eachcompartment. The release of the drug content in each compartment can becontrolled by the permeability, degradability or erodibility of theplug.

FIG. 16B shows the release profiles of the APIs from the dosage formillustrated in FIG. 16A.

FIG. 17A shows an exemplary dosage form having a substrate forming fourcompartments. Each compartment is loaded with a drug content.

FIG. 17B shows the release of the APIs from a dosage form having asubstrate consisted of four drug content embedded segments.

FIG. 17C shows the controlled release of the APIs from the dosage formillustrated in FIG. 17A.

FIG. 18A is a schematic diagram of the drug form having a substrateforming a pie-shaped compartment.

FIG. 18B is a photograph of a drug release processes of the drug formillustrated in FIG. 18A.

FIG. 18C shows release percentage curve of benzoic acid and PEG8000 fromthe dosage form of FIG. 18A.

FIG. 19A shows the perspective view of a dosage form that contains twocompartments.

FIG. 19B shows the cross-sectional view of the dosage form of FIG. 19A.

FIG. 19C shows an exemplary release profile of the dosage form of FIG.19A.

FIG. 19D shows another exemplary release profile of the dosage form ofFIG. 19A.

DETAILED DESCRIPTION OF THE INVENTION

In the Summary of the Invention above and in the Detailed Description ofthe Invention, and the claims below, and in the accompanying drawings,reference is made to particular features (including method steps) of theinvention. It is to be understood that the disclosure of the inventionin this specification includes all possible combinations of suchparticular features. For example, where a particular feature isdisclosed in the context of a particular aspect or embodiment of theinvention, or particular claim, that feature can also be used, to theextent possible, in combination with and/or in the context of otherparticular aspects and embodiments of the invention, and in theinvention generally.

The term “comprises” and grammatical equivalents thereof are used hereinto mean that other components, ingredients, steps, etc. are optionallypresent. For example, an article “comprising” (or “which comprises”)components A, B, and C can consist of (i.e., contain only) components A,B, and C, or can contain not only components A, B, and C but also one ormore other components.

Where reference is made herein to a method comprising two or moredefined steps, the defined steps can be carried out in any order orsimultaneously (except where the context excludes that possibility), andthe method can include one or more other steps which are carried outbefore any of the defined steps, between two of the defined steps, orafter all the defined steps (except where the context excludes thatpossibility).

Where a range of value is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictate otherwise, between the upper and lower limitof that range and any other stated or intervening value in that statedrange, is encompassed within the disclosure, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the disclosure.

The term “at least” followed by a number is used herein to denote thestart of a range beginning with that number (which may be a range havingan upper limit or no upper limit, depending on the variable beingdefined). For example, “at least 1” means 1 or more than 1. The term “atmost” followed by a number is used herein to denote the end of a rangeending with that number (which may be a range having 1 or 0 as its lowerlimit, or a range having no lower limit, depending upon the variablebeing defined). For example, “at most 4” means 4 or less than 4, and “atmost 40%” means 40% or less than 40%. In this disclosure, when a rangeis given as “(a first number) to (a second number)” or “(a firstnumber)−(a second number),” this means a range whose lower limit is thefirst number and whose upper limit is the second number. For example, 2to 10 millimeters means a range whose lower limit is 2 millimeters, andwhose upper limit is 10 millimeters.

It will be appreciated that for simplicity and clarity of illustration,where appropriate, reference numerals have been repeated among thedifferent figures to indicate corresponding or analogous elements. Inaddition, numerous specific details are set forth in order to provide athorough understanding of the embodiments described herein. However, theembodiments described herein can be practiced without these specificdetails. In other instances, methods, procedures and components have notbeen described in detail so as not to obscure the related relevantfunction being described. Also, the description is not to be consideredas limiting the scope of the implementations described herein. It willbe understood that descriptions and characterizations of the embodimentsset forth in this disclosure are not to be considered as mutuallyexclusive, unless otherwise noted.

Controlled Release Dosage Form

Conventional solid dosage forms, e.g., compressed tablets, are composedof a substrate where active drug ingredient is dissolved or embedded(FIG. 1A). Currently conventional solid dosage forms exhibit first-orderdrug release profile (FIG. 1B) where the plasma level of the drugincreases rapidly to an extremely high level after administration andthen decreases exponentially (see FIG. 1C). This poses disadvantagessuch as minimal therapeutic efficacy due to reduced drug levels or drugtoxicity which can occur at high concentrations. This type of drugrelease does not allow for appropriate plasma drug level balance. Theinstant invention relates to modified or controlled release oral drugdelivery system, which offers advantages over conventional systems,including increased patient compliance, selective pharmacologicalaction, reduced side effects and reduced dosing frequency. Controlledrelease offers prolonged delivery of drugs and maintenance of plasmalevels within a therapeutic range. For example, a drug delivery systemexhibiting zero-order drug release profile (FIG. 1D) allows for aconstant quantity of drug to be release over an extended period of time,resulting in uniform and sustained drug delivery. As a result,zero-order release profile may be desired in antibiotic delivery, thetreatment of hypertension, pain management, antidepressant delivery andnumerous other conditions that require constant plasma drug levels.

Therefore, one aspect of the present disclosure provides a stable solidpharmaceutical dosage form for oral administration, which has acontrolled release profile. In certain embodiments, the dosage formincludes a substrate forming at least one compartment and a drug contentloaded into the compartment. The dosage form is so designed that therelease of the active pharmaceutical ingredient of the drug content canbe controlled, e.g., by opening the compartment in a predeterminedmanner.

A. Substrate

As used herein, “substrate” refers to a structure in which a drug isenclosed or embedded. The substrate of a dosage form of the instantinvention can be of any size and shape that are suitable for oraladministration. In certain embodiments, the substrate is a flat roundtablet having a diameter of around 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8mm, 9 mm, 10 mm, 11 mm 12 mm. In certain embodiments, the substrate isan oval tablet having a dimension of around a mm×b mm, wherein a is 5 to15 and b is 2 to 10. In certain embodiments, the substrate has a capsuleshape.

In certain embodiments, the substrate is made of a hydrophilic polymer(e.g., hydroxypropylmethylcellulose (HPMC) and poly(ethylene oxide)(PEO)), a hydrophobic polymer (e.g., ethylcellulose (EC)), a swellablepolymer, a non-swellable polymer, a porous polymer, a non-porouspolymer, an erodible polymer, or a non-erodible polymer.

In certain embodiments, the dosage form has a monolithic substrate. Incertain embodiments, the substrate consists of several pieces, eachpiece made of the same or different material.

In certain embodiments, the substrate is made of a thermoplasticmaterial. As used herein, a “thermoplastic material” refers to amaterial having the ability to be shaped using heat and pressure. Incertain embodiments, the thermoplastic materials may, for example, behydrophilic, gel-forming materials, from which drug content releaseproceeds mainly by diffusion, or hydrophobic materials, from which drugcontent release proceeds mainly by diffusion from the pores in thesubstrate. Polymers, particularly cellulose ethers, cellulose estersand/or acrylic resins can be used as hydrophilic thermoplasticmaterials. Ethylcellulose, hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxymethylcellulose, poly(meth)acrylic acidand/or the derivatives thereof, such as the salts, amides or estersthereof are suitable for use as thermoplastic materials. Physiologicallyacceptable, hydrophobic materials that are known to the person skilledin the art, such as mono- or diglycerides of C12-C30 fatty acids and/orC12-C30 fatty alcohols and/or waxes or mixtures thereof may be used asthermoplastic material. Substrate prepared from hydrophobic materials,such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fattyalcohols or corresponding esters or ethers or mixtures thereof are alsoenvisioned.

In certain embodiments, the thermoplastic material is selected from thegroup consisting of polyvinyl caprolactam-polyvinyl acetate-polyethyleneglycol graft copolymer 57/30/13, polyvinylpyrrolidone-co-vinyl-acetate(PVP-VA), polyvinylpyrrolidone-polyvinyl acetate copolymer (PVP-VA)60/40, polyvinylpyrrolidone (PVP), polyvinyl acetate (PVAc) andpolyvinylpyrrolidone (PVP) 80/20, polyethylene glycol-polyvinyl alcoholgraft copolymer 25/75, kollicoat IR-polyvinyl alcohol 60/40, polyvinylalcohol (PVA or PV-OH), poly(vinyl acetate) (PVAc), poly(butylmethacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methylmethacrylate) 1:2:1, poly(dimethylaminoethylmethacrylate-co-methacrylicesters), poly(ethyl acrylate-co-methylmethacrylate-co-trimethylammonioethyl methacrylate chloride),poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1,poly(methacrylic acid-co-methylmethacrylate) 1:2, poly(methacylicacid-co-ethyl acrylate) 1:1, poly(methacylic acid-co-methylmethacrylate) 1:1, poly(ethylene oxide) (PEO), poly(ethylene glycol)(PEG), hyperbranched polyesteramide, hydroxypropyl methylcellulosephthalate, hypromellose phthalate, hydroxypropyl methylcellulose orhypromellose (HMPC), hydroxypropyl methylcellulose acetate succinate orhypromellose acetate succinate (HPMCAS), poly(lactide-co-glycolide)(PLGA), carbomer, poly(ethylene-co-vinyl acetate), ethylene-vinylacetate copolymer, polyethylene (PE), and polycaprolactone (PCL),hydroxyl propyl cellulose (HPC), Polyoxyl 40 Hydrogenerated Castor Oil,Methyl cellulose (MC), Ethyl cellulose (EC), Poloxamer, hydroxypropylmethylcellulose phthalate (HPMCP), Poloxamer, Hydrogenated Castor &Soybean Oil, Glyceryl Palmitostearate, Carnauba Wax, polylactic acid(PLA), polyglycolic acid (PGA), Cellulose acetate butyrate (CAB),Colloidal Silicon, Dioxide, Sucrose, Glucose, Polyvinyl AcetatePhthalate (PVAP) and a combination thereof.

Properties and sources of various thermoplastic materials are listed inTable 1.

In certain embodiments, the thermoplastic material allows the dosageform to be made using an additive method such as fused depositionmodeling (FDM). In certain embodiments, the substrate can be made byusing a three-dimensional printer (3D printer) configured to extrudingthe thermoplastic material. Typically, the thermoplastic material ismelted in the 3D printer before being extruded to form the substrate. Incertain embodiment, appropriate extruders include without limitation,single or twin screw extruders with the temperature within the extruderat a range from 50° C. to 180° C. and from 80° to 140° C. In general,the extrusion process can be conducted at temperatures 10° to 40° C.above the glass transition (Tg) of the thermoplastic material. Once at asuitable temperature for use in the three-dimensional printer, thethermoplastic material can be deposited to the three-dimensionalprinting surface. The shape and size of the substrate and thecompartment fabricated by the thermoplastic material can be controlledby programming the three-dimensional printing process.

In certain embodiments, the material of the substrate can be so selectedto control the release profile of a drug. For example, the substrate ismade of a material having desired erosion/dissolution rate, permeationrate so that when administered the compartment can be opened in apredetermined manner, and the drug content is release from thecompartment at desired rate. In certain embodiments, the substrate iserodible or dissolvable and is embedded with an active pharmaceuticalingredient (API). The API is released when the substrate is eroded ordissolved

The release of the drug content can also be controlled by adjusting thethickness of the substrate. For example, the substrate forming acompartment is made of a soluble material. The opening of thecompartment, thus the release of the drug content loaded within can becontrolled by adjusting the thickness of the walls that enclose thecompartment. The thicker the wall, the slower the compartment is open,and the later the drug content is released.

B. Compartment

In certain embodiment, the dosage form disclosed herein contains atleast one compartment within the substrate. As used herein,“compartment” refers to a space, part or room marked or partitioned offby the substrate. A compartment can be closed or be open (e.g., havingan aperture or a passageway). A compartment can be of any geometrysuitable for loading drug contents. In certain embodiments, thecompartment has a shape selected from the group consisting of a pieshape, a cone shape, a pyramid shape, a cylindrical shape, a cubic orcuboidal shape, a triangular or polygonal prism shape, a tetrahedron anda combination thereof.

In certain embodiments, containing a compartment in the dosage form canincrease its retention in the gastro intestinal tract. FIG. 2Aillustrates an exemplary dosage form having a substrate forming acompartment where drug content is loaded. Referring to FIG. 2A, a dosageform 100 has a compartment 102 formed by a substrate 101. A drug content103 is loaded in the compartment 102 by linking to the internal wall ofthe compartment 102. The compartment 102 can provide a floating effectto the dosage form and thereby extend its residence time in the stomachor in an aqueous or acidic environment. The residency time can be afunction of the erosion/dissolution rate of the materials of thesubstrate and result in a sustained release of API as shown in FIG. 2B.

FIG. 3 illustrates another exemplary dosage form with increasedresidence in the gastro intestinal tract. Referring to FIG. 3, a dosageform 200 has a configuration that the compartment 202 contains a seconddosage form 203 (e.g., a tablet) freely moving within the compartment202. The gastro intestinal residence time of a dosage form is limited.Using floating systems can allow the dosage form to stay in stomach andcontinuously release the drug at the upper part of GI tract and maximizethe absorption in small intestine.

In certain embodiments, the shape of the compartment is uniquely createdso that the drug content can be released at a controlled rate. Incertain embodiments, the compartment has a shape selected from the groupconsisting of a wedge shape, a pie shape, a cone shape, a pyramid shape,a cylindrical shape, a cubic or cuboidal shape, a triangular orpolygonal prism shape, a tetrahedron and a combination thereof.

In one embodiment, the compartment of the dosage form has differentgeometric shape. FIG. 4A shows an exemplary dosage form having asubstrate forming a compartment of pie shape. FIG. 4B shows an exemplarydosage form having a substrate forming multiple compartments containingvarious sized openings. FIG. 4C shows an exemplary dosage form having asubstrate forming an angled compartment. FIG. 4D shows an exemplarydosage form having a substrate forming multiple compartments ofdifferent sized radius.

The shape of the compartment can be used to control the release profileof the dosage form. For example, R. A. Lipper and W. I. Higuichidescribed a delivery system that provides zero-order release profile,which is illustrated in FIG. 5. FIG. 5 shows a cross-sectional view ofthe delivery system having a pie-shaped compartment. The compartmentcommunicates with the environment through a small opening. Thecompartment is loaded with a drug content that dissolves to release anAPI. The API is then released to the environment through the smallopening. The dissolution rate of the drug content positively correlatesto the area of the dissolution boundary of the drug content (theinterface between the drug content and the space of the compartment). Onthe other hand, the diffusion rate of the API into the environment isnegatively correlates to the diffusion path length λ. As a result, asthe drug content dissolves, the area of the dissolution boundaryincreases, and the dissolution rate of the drug content increases. Onthe other hand, the diffusion path length λ increases as the drugcontent dissolves. So the API released in the compartment needs to betransported a longer length to diffuse out of the dosage form. It isassumed that the dosage form can be so designed to provide a zero-orderrelease kinetics (R. A. Lipper and W. I. Higuchi (1977) Analysis oftheoretical behavior of a proposed zero-order drug delivery system. J.Pharm Sci 66(2): 163-4; D. Brooke and R. J. Washkuhn (1977) Zero-orderdrug delivery system: theory and preliminary testing. J Pharm Sci.66(2):159-162).

C. Drug Content

As used herein, the term “drug content” refers to a compositioncomprising one or more active ingredient, including activepharmaceutical ingredient (API), cosmetic agent, biological agent,diagnostic agent and reagent for scientific experiments.

As used herein, an API refers to an ingredient in a pharmaceutical drugthat is biologically active. In certain embodiments, the API is selectedfrom the groups consisting of local anesthetics, antiepileptic drugs andanticonvulsants, anti-Alzheimer's disease drugs, analgesics,antipodagric, anti-hypertensive drugs, antiarrhythmic drugs, diureticdrugs, drugs for treating liver diseases, drugs for treating pancreaticdiseases, antihistamine drugs, anti-allergic drugs, glucocorticoiddrugs, sex hormone drugs and contraceptive drugs, hypoglycemic drugs,anti-osteoporosis drugs, antibiotics, sulfonamides, quinolones, andother synthetic antibacterial drugs, anti-tuberculous drugs, antiviraldrugs, anti-neoplasm drugs, immune-modulators, cosmetically activeagents, traditional Chinese medicine (TCM) and TCM extracts.

In certain embodiments, the API is selected from the groups consistingof (R)-folitixorin, lidocaine, 11-di-deutero-ethyllinoleate,16-dehydro-pregnenolone, 17-beta-estradiol, 2-iminobiotin,3,5-diiodothyropropionicacid, 5-fluoro-2-deoxycytidine,6-mercaptopurine, edotreotide, abacavir, abalone haemocyanin,abametapir, abediterol, abemaciclib, abexinostat, abiraterone,acalabrutinib, acamprosate, acamprosatecalcium, acarbose, acebilustat,aceclidine, aceclofenac, acehytisine hydrochloride, acemannan,aceneuramic acid, acetaminophen, acetylcysteine, acetylkitasamycin,acetyl-L-carnitinehydrochloride, acetylsalicylicacid, aciclovir,acipimox, acitazanolast, acitretin, aclidinium, aclidinium bromide,acolbifene, acorafloxacin, acotiamide, acrivastine, actarit, adapalene,adapalene, adefovirdipivoxil, ademetionine, adoair, afatinib,afimoxifene, afuresertib, agomelatine, aildenafilcitrate, aladorian,alalevonadifloxacin mesylate, alarelin acetate, alatrofloxacin mesylate,albendazole, albuterol sulfate, albuterpenoids, alcaftadine,aldoxorubicin, alectinib, alendronate, alendronate sodium, alendronatesodiumhydrate, alendronic acid, alfacalcidol, alfaxalone, alfentanil,alfuzosin, alisertib, aliskiren, alisporivir, alitretinoin, allantoin,allisartanisoproxil, allopurinol, almotriptan, alogliptin, alogliptinbenzoate, alosetron, alpelisib, alphaketoglutarate, alphalipoic acid,alpha-lantitrypsin, alpha-cyclodextrin-stabilized sulforaphane,alprazolam, alprostadil, alprostadil alfadex, altiratinib, altretamine,altropane, aluminum sulfate, alvimopan, alvocidib, amantadine,amantadine hydrochloride, ambrisentan, ambroxol, ambroxol hydrochloride,amcasertib, amfetamine, amfetamine polistirex, amifampridine,amifampridine phosphate, amifostine, amikacin, amiloride,aminolevulinic, aminolevulinic acid, aminolevulinic acid hydrochloride,aminopterin, amiodarone, amiselimod, amisulpride, amitifadinehydrochloride, amitriptyline, amlexanox, amlodipine, amlodipine,amlodipinebesilate, amlodipine besylate, amlodipine camsylate,amlodipine maleate, amlodipine nicotinate, amlodipine orotate, ammoniumlactate, amodiaquine, amorolfine, amosulalol, amoxicillin, amoxicillinhydrate, amphetamine, amphetamine aspartate, amphetamine sulfate,amphotericinB, amphotericinB cholesterylsulfate, amphotericinB lipidcomplex, ampicillin sodium, ampiroxicam, amrinone, amrubicin,amtolmetinguacil, anacetrapib, anagliptin, anagrelide, anamorelin,anastrozole, ancrod, androgen, andrographolide, anecortave,anidulafungin, aniracetam, anistreplase, anlotinib, antazoline,antiandrogens, antineoplaston A-10, antineoplaston AS2-1, antofloxacinhydrochloride, antroquinonol, apabetalone, apalutamide, apatinibmesylate, apaziquone, apilimod mesylate, apixaban, apomorphine,apomorphine hydrochloride, apremilast, aprepitant, apricitabine,aramchol, aranidipine, arasertaconazole, arasertaconazol enitrate,arbaclofen, arbaclofen placarbil, arbekacin, arbekacin sulfate,ardeparin sodium, arformoterol, argatroban, arhalofenate, arimoclomol,aripiprazole, aripiprazole lauroxil, armodafinil, arsenictrioxide,arsenious acid, artefenomel mesylate, artemether, artemotil, artenimol,arterolane maleate, artesunate, Artiss, asapiprant, asenapine,asimadoline, astodrimer, astragaloside, asunaprevir, ataciguat,ataluren, atazanavir, atazanavir sulfate, atenolol, atomoxetine,atorvastatin, atorvastatin calcium, atorvastatin strontium, atovaquone,atrasentan, atropine, auranofin, auriclosene, avacincaptadpegol sodium,avacopan, avanafil, avatrombopag, avibactam, avibactam sodium, AvidinOx,aviptadil, avitinib, avoralstat, axelopran, axitinib, azacitidine,azacytidine, azasetron, azelaicacid, azelastine, azelastinehydrochloride, azeliragon, azelnidipine, azilsartan, azilsartanmedoxomil potassium, azilsartan trimethylethanolamine, azimilide,azithromycin, azithromycin lactobionate, aztreonam, aztreonam lysine,azvudine, baclofen, bafetinib, Baicalein, baicalin, BAK-freelatanoprost,balofloxacin, balsalazide, balsalazide sodium, bambuterol, barasertib,bardoxolone methyl, baricitinib, barnidipine, basmisanil, batefenterolsuccinate, bazedoxifene, beclabuvir, beclometasone dipropionate,beclomethasone dipropionate, bedaquiline, bedoradrine, belinostat,beloranib, belotecan, bempedoic acid, benapenem, benazepril,bencycloquidium bromide, bendamustine, bendamustine hydrochloride,benidipine, benserazide, bentamapimod, benzalkonium chloride,benzhydrocodone, benznidazole, benzocaine, benzoylperoxide,benzydamineHCL, bepotastine, bepotastine calciumdihydrate, bepotastinesalicylate, beractant, beraprost sodium, besifloxacin, besifovir,besipirdine, beta-elemene, betahistine, betaine anhydrous,betamethasone, betamethasone butyrate propionate,betamethasonedipropionate, betamethasone valerate, betamipron,betaxolol, betaxolol hydrochloride, bethanechol, betrixaban,bevacizumab, bexagliflozin, bexarotene, bezafibrate, biafungin,biapenem, bicalutamide, bicizar, bictegravir, bicyclol, bilastine,bimatoprost, binimetinib, biotin, birabresibdihydrate, biskalcitratepotassium, bismuth subgallate, bismuthyl ecabet, bisnorcymserine,bisoprolol, bisoprolol fumarate, bitespiramycin, bixalomer, bleomycin,blonanserin, boanmycin hydrochloride, boceprevir, bortezomib, bosentan,bosentan hydrate, bosutinib, bovactant, brexpiprazole, briciclib sodium,brigatinib, brilacidin, brimapitide, brimonidine, brincidofovir,brinzolamide, brivanibalaninate, brivaracetam, brivudine, brolucizumab,bromazepam, bromfenac, bromfenac sodium, bromocriptine, bronchostat,brotizolam, bryostatin-1, bucindolol, bucladesine, budesonide, budipine,buflomedil, bulaquin, bunazosin, buparlisib, bupivacaine, bupivacainehydrochloride, buprenorphine, buprenorphine hydrochloride, bupropion,bupropion hydrochloride, burixafor, buserelin acetate, buspirone,buspirone hydrochloride, busulfan, busulfex, butenafine, butorphanoltartrate, butylphthalide, cabazitaxel, cabergoline, cabotegravir,cabozantinib S-malate, cadazolid, cadrofloxacin, caffeine, caffeinecitrate, cafnea, cafusertib hydrochloride, calcipotriol, calcitriol,calcium acetate, calciumfolinate, calcium levofolinate, calciumpolycarbophil, calfactant, calmangafodipir, calsurf, camicinal, camostatmesylate, camptothecin, canagliflozin, candesartan, candesartancilexetil, canfosfamide, cangrelor, cannabidiol, capecitabine,capmatinib, capsaicin, captopril, carbamazepine, carbetocin, carbidopa,carbinoxamine, carbocysteine, carboplatin, cardidopa, carfilzomib,carglumicacid, cariprazine, carisbamate, carmustine, carotegastmethyl,carteolol, carteolol hydrochloride, carumonam, carvedilol,carvedilolphosphate, caspofungin, catechin, cebranopadol, cediranib,cefaclor, cefadroxil, cefathiamidine, cefazolin sodium pentahydrate,cefcapene, cefdinir, cefditorenpivoxil, cefepime, cefepimedihydrochloride, cefetametpivoxil hydrochloride, cefiderocol,cefilavancin, cefminox, cefoperazone, cefoperazone sodium, cefoselis,cefotaxime, cefotaxime sodium, cefotiam, cefozopran, cefpirome,cefpodoxime, cefprozil, ceftaroline, ceftaroline fosamil, ceftazidime,ceftibuten, ceftobiprole medocaril, ceftolozane sulfate, ceftriaxone,ceftriaxone sodium, cefuroxime, cefuroxime sodium, celecoxib,celgosivir, celiprolol, cellprotect, cenestin, cenicriviroc,censavudine, centanafadine, cephalosporin, ceralifimod, cerdulatinib,ceritinib, ceriumnitrate, cetilistat, cetirizine, cetraxate, cevimeline,chenodeoxycholic acid, chlocibutamine, chlorhexidine, chlormadinoneacetate, chlorogenicacid, chloroquine, chloroxoquinoline,chlorpheniramine, chlorpheniramine maleate, chlorpheniramine polistirex,chlortalidone, chlorthalidone, cholecalciferol, cholic acid, cholinealfoscerate, choline diepalrestat, choline fenofibrate, ciclesonide,ciclopiroxolamine, ciclosporin, cidofovir, cidoxepin, cilastatin,cilazapril, cilnidipine, cilostazol, cimetidine, cinacalcet, cinepazidemaleate, cinhyaluronate sodium, cinitapride tartrate, cipargamin,ciprofibrate, ciprofloxacin, ciprofloxacin hydrochloride, ciraparantag,circadin, cisatracurium besilate, cisplatin, citalopram, citalopramhydrobromide, citicoline, citrulline, cladribine, clarithromycin,clavulanate potassium, clavulanic acid, clazosentan, clevidipine,clevudine, clindamycin, clindamycin hydrochloride, clindamycinphosphate, clioquinol, clobazam, clobetasolpropionate,clobetasolpropionatefoam, clodronic acid, clofarabine, clofazimine,clomipramine, clomipramine hydrochloride, clonazepam, clonidine,clonidine hydrochloride, clopidogrel, clopidogrel besylate, clopidogrelbisulfate, clopidogrel camsylate, clopidogrel hydrogensulfate,clopidogrel napadisilate, clopidogrel resinate, clotrimazole, clozapine,cobamamide, cobicistat, cobimetinib, cobiprostone, codeine, codeinepolistirex, colchicine, colecalciferol, colesevelam, colestilan,colforsin daropate, colfosceril palmitate, colistimethate sodium,conivaptan, copanlisib, copperhistidine, cortexolone 17alpha-propionate,cositecan, crenolanib, cridanimod sodium, crisaborole, crizotinib,crofelemer, crolibulin, cromoglicic acid, cromolyn sodium, cutamesinedihydrochloride, cyanocobalamin, cyclizine lactate, cyclobenzaprinehydrochloride, cyclophosphamide, cyclophosphamide monohydrate,cyclosporin, cyproterone, cyproterone acetate, cytarabine, cytarabineocfosfate, dabigatran etexilate, dabrafenib, daclatasvir, dacomitinib,dalbavancin, dalcetrapib, dalfampridine, dalfopristin, dalteparinsodium, danaparoid sodium, danazol, danirixin, danoprevir, dantrolenesodium, danusertib, dapaconazole, dapagliflozin, dapagliflozinpropanediol, dapiprazole, dapivirine, dapoxetine, daprodustat, dapsone,darifenacin, darinaparsin, darunavir, dasabuvir, dasatinib, dasotraline,daunorubicin, decitabine, decuprate, defactinib, deferasirox,deferiprone, deferoxamine mesylate, deflazacort, deflexifol,delafloxacin, delamanid, delapril, delapril hydrochloride, delavirdine,denibulin, deoxyandrographolide, dermatansulfate, desflurane,desipramine hydrochloride, desloratadine, desmopressin, desmopressinacetate, desogestrel, desonide, desvenlafaxine, deudextromethorphanhydrobromide, deuteporfin, deuterated levodopa, deuteratedvenlafaxine,deutetrabenazine, dexamethasone, dexamethasone acetate, dexamethasonecipecilate, dexamethasone palmitate, dexamethasone sodiumphosphate,dexamfetamine, dexanabinol, dexferrum, dexketoprofen trometamol,dexlansoprazole, dexmedetomidine, dexmethylphenidate, dexpramipexole,dexrazoxane, dexsotalol, dextroamphetamine saccharate, dextroamphetaminesulfate, dextromethorphan, dextromethorphan hydrobromide,dextropropoxyphene, diacerein, diamorphine hydrochloride,dianhydrogalactitol, diazepam, diazoxidecholine, diclofenac, diclofenacpotassium, diclofenac sodium, diclofenamide, dicycloplatin, didanosine,dienogest, difluprednate, digoxin, dihomogamma-linolenic acid,dihydroergocristine, dihydroergotamine, dihydroergotamine mesylate,diltiazem, diltiazem hydrochloride, dimesna, dimethyl fumarate,dimiracetam, dinoprostone, diphenylcyclopropenone, dipraglurant,dipyridamole, diquafosoltetra sodium, dirithromycin, disufenton sodium,disulfiram, dithranol, d-methadone, docarpamine, docetaxel, dociparstat,docosanol, dofetilide, dolasetron, dolutegravir, domperidone, donafenibtosylate, donepezil, donepezil hydrochloride, dopamine, doravirine,doripenem, dorzolamide, dorzolamide hydrochloride, dosmalfate,doxacurium chloride, doxazosin, doxazosin mesylate, doxepinhydrochloride, doxercalciferol, doxifluridine, doxofylline, doxorubicin,doxorubicin hydrochloride, doxycycline, doxycycline hyclate, doxylaminesuccinate, dronabinol, dronedarone, drospirenone, droxidopa, D-tagatose,duloxetine, duloxetine hydrochloride, dutasteride, duvelisib, ebastine,eberconazole, ebselen, ecabet, econazolenitrate, ecopipam, edaravone,edivoxetine, edonerpic maleate, edoxaban, efatutazone, efavirenz,efinaconazole, eflornithine, efonidipin hydrochloride, egualen sodium,eicosapentaenoic acid monoglycerides, elafibranor, elagolix,elamipretide, elbasvir, eldecalcitol, eleclazine, elesclomol sodium,eletriptan, eliglustattartrate, elobixibat, eltrombopag, eluxadolinedihydrochloride, elvitegravir, emdogain, emedastine, emeramide,emixustat, emodepside, empagliflozin, emricasan, emtricitabine,enalapril, enalaprilmaleate, enasidenib, encenicline, enclomifenecitrate, encorafenib, endoxifen, enobosarm, enoxacin gluconate,enoxaparin sodium, enprostil, entacapone, entasobulin, entecavir,entecavir maleate, entinostat, entospletinib, entrectinib, enzalutamide,enzastaurin, epacadostat, epalrestat, eperisone, epetraborole, ephedrinesulfate, epinastine hydrochloride, epinephrine, epirubicin, epirubicinhydrochloride, episalvan, epitinib, eplerenone, epoprostenol,epristeride, eprodisate, eprosartan, eptaplatin, eravacycline,erdafitinib, erdosteine, eribulin mesylate, erlotinib, ertapenem,erteberel, ertugliflozin, erythromycin, erythromycin acistrate,erythromycin stinoprate, escitalopram, esketamine, esketaminehydrochloride, eslicarbazepine acetate, esmolol hydrochloride,esomeprazole, esomeprazole magnesium, esomeprazole strontium,esomeprazole, estetrol, estradiol, estradiol acetate, estradiolcypionate, estradiol valerate, estrodiol, estrogen, esuberaprost sodium,eszopiclone, etamicastat, ethambutol hydrochloride, ethaselen,ethinylestradiol, ethylhydrogenfumarate calcium, ethylhydrogenfumaratemagnesium, ethylhydrogenfumara tezinc, ethynylestradiol, etidronicacid,etimicin sulfate, etirinotecanpegol, etizolam, etodolac, etonogestrel,etoposide, etoposide phosphate, etoricoxib, etravirine, etripamil,eupatilin, evenamide hydrochloride, everolimus, evofosfamide,evogliptin, exemestane, exendin(9-39), exeporfinium chloride,ezatiostat, ezetimibe, ezutromid, fadolmidine, fadrozole, faldaprevir,falecalcitriol, famciclovir, famitinib, famotidine, fampridine,faropenem, fasitibant chloride, fasoracetam, fasudil, fasudilhydrochloride, fasudil mesylate, favipiravir, febarbamate, febuxostat,fedovapagon, felbamate, felbinac trometamol, felodipine, femitra,fenfluramine hydrochloride, fenobam, fenofibrate, fenofibric acid,fenoldopam, fenoterol, fenretinide, fentanyl, fentanyl citrate,fenticonazole, fermagate, ferriccitrate, ferricmaltol, ferumoxytol,fesoterodine fumarate, fevipiprant, fexinidazole, fexofenadine,fibrinsealant, fibrinogen, fibrinogensealant, fidaxomicin, filanesib,filgotinib, filociclovir, fimaporfin, fimasartan, finafloxacin,finafloxacin hydrochloride, finasteride, finerenone, fingolimod,fipamezole, firtecanpegol, flecainide, fleroxacin, flibanserin,flomoxef, floxuridine, fluazolepali, fluconazole, fludarabine,flumatinib, flumazenil, flunisolide, fluocinolone acetonide,fluocinonide, fluorapacin, fluorouracil, fluoxetine, fluoxetinehydrochloride, flupirtine, flurbiprofen, flurbiprofenaxetil,flurbiprofen sodium, flurithromycin, fluticasone, fluticasone furoate,fluticasone propionate, flutrimazole, fluvastatin, fluvoxamine, folicacid, folinate, foliumginkgo, fomepizole, fonadelpar, fondaparinuxsodium, foretinib, formestane, formoterol, formoterol fumarate,forodesine, fosamprenavir, fosaprepitant, fosbretabulin, fosbretabulindisodium, fosfluconazole, fosfomycin, fosfomycindi sodium,fosfomycintrometamol, fosinopril, fosinopril sodium, fosmidomycin,fosphenytoin, fospropofol, fosravuconazole, fostamatinib, fostemsavirtromethamine, fotagliptin benzoate, fotemustine, frovatriptan,fruquintinib, fudosteine, fulvestrant, funapide, furosemide, fusidicacid, gabapentin, gabapentinenacarbil, gabexate mesylate, gacyclidine,gadobutrol, gadoversetamide, gadoxetate disodium, galantamine,galeterone, galidesivir, gallium nitrate, galunisertib, gambogic acid,ganaxolone, ganciclovir, ganetespib, ganirelix acetate, garenoxacin,gatifloxacin, gatifloxacin mesylate, gedatolisib, gefitinib, gemcabene,gemcitabine, gemcitabine hydrochloride, gemfibrozil, gemifloxacin,gemigliptin, gemigliptintartaric acid, genistein, gentamicin,gentiopicrin, gepirone, gepotidacin, gestodene, gestrinone, timololmaleate, gilteritinib, gimeracil, ginsenosideC-K, ginsenosideRg3,givinostat, glasdegib, glatiramer acetate, glecaprevir, glesatinibglycolate, glibenclamide, gliclazide, glimepiride, glipizide,glufosfamide, glutamine, glutathionarsenoxide, glycerol phenylbutyrate,glycopyrronium, glycopyrronium bromide, glycopyrronium tosylate,glycyrrhizi cacid, ganglioside, golotimod, gosogliptin, granisetron,granisetron hydrochloride, grazoprevir, guaifenesin, guaimesal,guanfacine, gusperimus trihydrochloride, haemophilusinfluenzae,halobetasol propionate, halofantrine, halometasone, healon,hematoporphyrin, hemearginate, hemocoagulase acutus, heparin, Herbiron,hetrombopag, hextend, higenaminehydrochloride, histaminedihydrochloride, HPPHphotosensitizer, humanapotransferrin,humanplasminogen, huperzineA, hyaluronate sodium, hydralazine,hydrochloride, hydrochlorothiazide, hydrocodone, hydrocodone bitartrate,hydrocodone polistirex, hydrocortisone, hydrogenperoxide, hydromorphone,hydromorphone hydrochloride, hydroxocobalamin, hydroxycarbamide,hydroxychloroquine, hydroxyprogesterone caproate, hydroxysaffloryellowA, hylastan, hypericin, hypoestoxide, ibandronate, ibandronicacid, iberogastN, ibodutant, ibrutinib, ibudilast, ibuprofen, ibutilide,ibutilide fumarate, icaritin, iclaprim, icosabutate, icosapent,icosapentethyl, icosapentethylester, icotinib hydrochloride,idalopirdine, idasanutlin, idebenone, idelalisib, idoxuridine,idronoxil, ifetroban, ifetrobansodium, iguratimod, ilansoprazole,ilaprazole, iloperidone, iloprost, iloprostbetadexclathrate, imatinib,imatinibmesylate, imeglimin, imidafenacin, imidapril, imidazolesalicylate, imidol hydrochloride, imigliptin dihydrochloride, imipenem,imiquimod, imisopasem manganese, imrecoxib, incadronic acid,incobotulinumtoxin, indacaterol, indacaterol maleate, indapamide,indeloxazine, Indimitecan, indinavir, indisetron, indometacin,indoramin, indotecan, indoximod, inecalcitol, infigratinib, Ingavirin,ingenolmebutate, inhaled sodium nitrite, ferric carboxymaltose, inosine,intepirdine, iodiconazole, ipatasertib dihydrochloride, ipragliflozin,ipratropium, ipratropium bromide, iptakalim, irbesartan, irinotecan,irinotecan hydrochloride, irinotecan sucrosofate, irofulven, ironisomaltoside1000, iron protein succinylate, irosustat, irsogladinemaleate, isavuconazonium chloride/sulfate, isodibut, isoflurane,isoniazid, isopropylunoprostone, isosorbidedi nitrate, isosorbidemononitrate, isosteviol, isothiafludine, isotretinoin, isradipine,istaroxime, istradefylline, itacitinib, itopride hydrochloride,itraconazole, ivabradine hemisulfate, ivabradine hydrochloride,ivacaftor, ivermectin, ivosidenib, aflibercept, ixabepilone, ixazomibcitrate, kallikrein, kangbeide, ketamine, ketanserin, ketoconazole,ketoprofen, ketorolac, ketorolac tromethamine, ketotifen, kevetrin,kukoamine Bmesylate, L-4-chlorokynurenine, lacidipine, lacosamide,lactitol, ladarixin, ladostigil, laflunimus, lafutidine, lamivudine,lamotrigine, landiolol, landiolol hydrochloride, laninamivir octanoate,lanoconazole, lansoprazole, lanthanum carbonate, lapatinib, laquinimod,laromustine, lasmiditan, lasofoxifene, latanoprost, latanoprostenebunod,lauflumide, ledipasvir, lefamulin, leflunomide, lemborexant,lenalidomide, lentinan, lentinansulfate, lentinanviral, lenvatinibmesylate, lercanidipine, lesinurad, leteprinim, letermovir, letrozole,leucine, leuprorelin acetate, levalbuterol, levalbuterol hydrochloride,levamisole, levamlodipine, levamlodipine besylate, levamlodipinemaleate, levetiracetam, levobupivacaine, levocabastine, levocabastinehydrochloride, levocarnitine, levocetirizine dihydrochloride, levodopa,levodoxazosin mesylate, levofloxacin, levoketoconazole, levomilnacipran,levonadifloxacin arginine salt, levonorgestrel, levonorgestrelbutanoate, levo-phencynonate hydrochloride, levornidazole, levorphanol,levosimendan, levothyroxine sodium, levotuss, L-glutamine, lidocaine,lifitegrast, ligustrazine hydrochloride, limaprost, linagliptin,linezolid, liothyronine, liothyronine sodium, lipobean, liposomalcurcumin, lipoteichoic acid, liranaftate, lisdexamfetamine, lisinopril,lisofylline, lisuridehydrogen maleate, lithiumcitrate, lithiumsuccinate,lixivaptan, lobaplatin, lobeglitazone, lodenafil carbonate, lofexidine,lomefloxacin, lomerizine, lomerizine dihydrochloride, lomitapide,lonafarnib, lonidamine, loperamide, loperamideoxide, lopinavir,loratadine, lorazepam, lorcaserin, lorediplon, lorlatinib,L-ornithineL-aspartate, lornoxicam, losartan, losartan potassium,losmapimod, loteprednoletabonate, lovastatin, loxapine, loxoprofen,L-praziquantel, lubiprostone, lucanthone, lucerastat, lucinactant,lucitanib hydrochloride, luliconazole, lumacaftor, lumateperone toluenesulfonate, lumefantrine, lumiracoxib, lunacalcipol, lurasidone,lurbinectedin, luseogliflozin hydrate, lusutrombopag, lysineacetylsalicylate, macimorelin, macitentan, mafenide, magnesiumcarbonate, magnesium isoglycyrrhizinate, mangafodipir, manidipine,manidipine dihydrochloride, mannitol, maraviroc, maribavir, marizomib,masilukast, masitinib, mavoglurant, maxacalcitol, mebendazole, mebiphon,mecamylamine, mecamylamine hydrochloride, mechlorethamine, mecobalamin,medroxyprogesterone, medroxyprogesteroneacetate, mefloquine, megestrol,megestrolacetate, meisuoshuli, melevodopa, meloxicam, melphalan,melphalanflufenamide hydrochloride, memantine, memantine hydrochloride,menadione sodium bisulfite, menatetrenone, mepacrine, mequinol,mercaptamine, mercaptamine bitartrate, mercaptamine hydrochloride,mercaptopurine, merestinib, meropenem, merotocin, mesalamine,mesalazine, metacavir, metadoxine, metamizolesodium, metaxalone,metergoline, metformin, metformin hydrochloride, methadone,methazolamide, methotrexate, methoxyflurane, methylaminolevulinatehydrochloride, methylnaltrexone bromide, methylnaltrexone,methylphenidate, methylphenidate hydrochloride, methylprednisolone,methylprednisolone aceponate, methylthioninium chloride, metirosine,metoclopramide, metoprolol, metoprolol succinate, metrifonate,metronidazole, metyrapone, mexiletine, mibefradil, miconazole,miconazole nitrate, midazolam, midazolam hydrochloride, midodrine,midostaurin, mifamurtide, mifepristone, migalastat, miglitol, miglustat,milnacipran, milrinone, miltefosine, minaprine, minocycline, minocyclinehydrochloride, minodronic acid, minoxidil, mirabegron, miriplatinhydrate, mirodenafil, mirodenafil hydrochloride, mirogabalin,mirtazapine, misoprostol, mitiglinide, mitomycin, mitoxantrone,mitoxantrone hydrochloride, mivotilate, mizolastine, mizoribine,mocetinostat dihydrobromide, moclobemide, modafinil, doxycycline,modipafant, moexipril, mofezolac, molidustat, molindone hydrochloride,momelotinib, mometasone, monepantel, monoammonium glycyrrhizinate,monobenzone, monosodium alphaluminol, monoterpene perillyl alcohol,montelukast, montelukast sodium, montmorillonite, moracizine,morinidazole, morphine, morphine glucuronide, morphine pitavastatin,morphine sulfate, morphothiadine mesilate, mosapride, motolimod,moxidectin, moxifloxacin, moxifloxacin hydochloride, moxonidine,moxonidine hydrochloride, mozavaptan, muparfostat sodium, mupirocin,mycobactovir, mycophenolatemofetil, myristylnicotinate, nabilone,nabiximols, nabumetone, N-acetylcysteine, nacystelyn, nadifloxacin,nadolol, nadroparin calcium, naftifine hydrochloride, naftopidil,nalbuphine, nalbuphine sebacate, naldemedine, nalfurafine, nalmefene,naloxegol, naloxone, naloxone hydrochloride, naltrexone, naltrexonehydrochloride, naluzotan, nandrolone decanoate, napabucasin,naphazoline, naphthoquine, naproxen, naproxen sodium, naquotinibmesylate, naratriptan, narlaprevir, nasapaque, nasaruplase,nastorazepide calcium, nateglinide, navamepent, nazartinib, nebivolol,necuparanib, nedaplatin, nedocromil, nelarabine, nelfinavir,nelotanserin, nemonapride, nemonoxacin, neoandrographolide,neosaxitoxin, neostigmine methylsulfate, nepadutant, nepafenac,nepicastat, nepolong, neramexane, neratinib, neridronic acid,netarsudil, netilmicin, netupitant, nevirapine, niacin, nicardipine,nicergoline, nicorandil, nicotiflorin, nicotine, nicotinicacid,nicousamide, nifedipine, nifekalant, nifeviroc, Nifurtimox, nifurzide,nikkomycin, nilotinib, nilutamide, nilvadipine, nimesulide, nimodipine,nimorazole, ningetinib, nintedanib, niraparib, nisoldipine,nitazoxanide, nitisinone, nitrendipine, nitricoxide, nitroglycerin,nitroglycerine, nizatidine, nokxaban, nolatrexed, nomegestrol acetate,norelgestromin, norepinephrine, norethindrone, norethindrone acetate,norethindrone enantate, norethisterone, norethisterone acetate,norfloxacin, norgestimate, noribogaine, norursodeoxycholic acid,obeticholicacid, octenidine, octohydroaminoacridine succinate,octreotide, octreotide hydrochloride, odalasvir, odanacatib, odiparcil,ofloxacin, olanzapine, olaparib, olesoxime, oliceridine, olmesartan,olmesartan cilexetil, olmesartan medoxomil, olodaterol, olodaterolhydrochloride, olopatadine, olopatadine hydrochloride, olprinone,olsalazine, oltipraz, omacetaxine mepesuccinate, omadacycline,omarigliptin, omaveloxolone, ombitasvir, omecamtivmecarbil,omega-3carboxylicacids, omeprazole, omigapil, omoconazole, onalespib,onapristone, ondansetron, ondelopran, opicapone, opipramol,methylphenidate, orcinoside, orilotimod, oritavancin, orlistat,ornithine phenylacetate, ornoprostil, ortataxel, orteronel, orthovisc,orvepitant, oseltamivir, osilodrostat, osimertinib, Osiris Phleumpratense, ospemifene, oteracil potassium, oteseconazole, oxaliplatin,oxaloacetic acid, oxandrolone, oxazepam, oxcarbazepine, oxfendazole,oxidizedglutathione sodium, oxiracetam, oxybutynin, oxybutyninhydrochloride, oxycodone, oxycodone hydrochloride, oxymetazoline,oxymetazoline hydrochloride, oxymorphone, oxytocin, ozagrel, ozagrelhydrochloride, ozagrelsodium, ozanimod, ozenoxacin, paclitaxel,paclitaxel poliglumex, pacritinib, palbociclib, paliperidone,paliperidone palmitate, palmidrol, palonosetron, palovarotene,pamidronate disodium, pancrelipase, panipenem, panobinostat,pantoprazole, paracetamol, parecoxib, paricalcitol, paritaprevir,parnaparin sodium, parogrelil, paromomycin, paroxetine, paroxetinehydrochloride hemihydrate, paroxetine mesylate, patiromer calcium,patupilone, pazopanib, pazufloxacin, pazufloxacin mesylate, pefcalcitol,peficitinib, pegylatedapo-filgrastim, pelubiprofen, pemafibrate,pemetrexed disodium, pemirolast, pemirolast potassium, pemirolastsodium, penciclovir, penehyclidine hydrochloride, pentamidine, pentetatecalcium trisodium, pentetatezinc trisodium, pentetrazol, pentosanpolysulfate sodium, pentostatin, pentoxifylline, peramivir, perampanel,perchlozone, peretinoin, perflenapent, perflubronemulsion,perfluorooctyl bromide, pergolide, perhexiline maleate, perifosine,perindopril, perindopril arginine, perospirone, pevonedistat,pexidartinib, PhagoBioDerm, phenchlobenpyrrone, phenethylisothiocyanate, phenoxybenzamine hydrochloride, phentermine, phenterminehydrochloride, phentolamine mesylate, phenylbutyrate, phenylephrine,phenylephrine hydrochloride, phenytoin, phosphazid, pibrentasvir,picibanil, picroliv, picropodophyllin, pidotimod, pilocarpine,pilocarpine hydrochloride, pilsicainide, pimasertib hydrochloride,pimavanserin, pimecrolimus, pimobendan, pinocembrin, pinometostat,pioglitazone, pioglitazone hydrochloride, pipamperone, pipecuronium,piperacillin, piperacillin sodium, piperaquine, piperaquine phosphate,piperidone hydrochloridum, piperine, piperphentonamine, piracetam,pirarubicin, pirfenidone, pirmenol, piromelatine, pirotinib, piroxicam,piroxicambetadex, pitavastatin, pitavastatin calcium, pitolisant,pixantrone, plazomicin, pleconaril, plerixafor, plinabulin, pocapavir,hydromorphone, podofilox, polaprezinc, polmacoxib, polydatin,polyoxidonium, pomaglumetad methionil, pomalidomide, ponatinib,ponesimod, porfimer sodium, posaconazole, posiphen, potassiumbicarbonate, potassium citrate, potassium clavulanate, poziotinib,pracinostat, pradefovir, pralatrexate, pramipexole, pramiracetam,pranlukast, pranlukast hydrate, prasterone, prasugrel, pravastatin,prazosin, prednimustine, prednisolone, prednisoloneacetate, prednisolonesodiumphosphate, prednisone, pregabalin, prempro, presatovir,pretomanid, previdersin, prexasertib, pridopidine, prilocaine,pritelivir, procaterol hydrochloride, prochlorperazine,prochlorperazinemaleate, profezyme, progesterone, progestogen,progestogendienogest, proguanil, promethazine, promitil, propafenone,propagermanium, propofol, propranolol, propranolol hydrochloride,prostat, proxodolol, prucalopride, prulifloxacin, prurisol,prussianblueinsoluble, pseudoephedrine, pseudoephedrine hydrochloride,puerarin, puquitinib mesylate, pyrazinamide, pyridoxaminedihydrochloride, pyridoxine hydrochloride, pyrimethamine, pyronaridine,pyrroltinibmaleate, quazepam, quetiapine fumarate, quetiapine,quinagolide hydrochloride, quinapril hydrochloride, quinidine sulfate,quinine sulfate, quinupristin, quisinostat, quizartinibdi hydrochloride,rabeprazole, rabeprazolesodium, rabeximod, racecadotril, radezolid,radotinib, ralfinamide, ralimetinib, ralinepag, raloxifene, raltegravir,raltitrexed, ramatroban, ramelteon, ramipril, ramosetron, ranitidine,ranitidine bismuth citrate, ranolazine, rasagiline, ravidasvirhydrochloride, raxatrigine, rebamipide, rebastinib, reboxetine,reboxetine mesylate, recilisib sodium, recoflavone, redaporfin,ibuprofen, naproxen, glycopyrronium bromide, refametinib, regorafenib,relebactam, relenopride, relugolix, remeglurant, remifentanil,remifentanil hydrochloride, remimazolam, remimazolam tosylate,remogliflozin etabonate, repaglinide, reparixin, repirinast, amlexanox,chlorcyclizine hydrochloride, bucillamine, guanabenz, mazindol,naltrexone, nitisinone, ondansetron, phacetoperane, retigabine,rosiglitazone, sodium phenylbutyrate, resiniferatoxin, resiquimod,resminostat, resveratrol, retagliptin, retapamulin, retigabine,retinoicacid, retosiban, revaprazan, revefenacin, reviparin sodium,rhein, rhenium-186 etidronate, ribavirin, ribociclib, ricolinostat,ridinilazole, ridostin, rifabutin, rifampicin, rifamycin, rifapentine,rifaximin, rigosertib sodium, rilapladib, rilpivirine, rilpivirinehydrochloride, riluzole, rimantadine, rimeporide, rimexolone, riociguat,ripasudil hydrochloride hydrate, risedronate sodium, risperidone,ritonavir, rivaroxaban, rivastigmine, rivipansel sodium, rizatriptan,rizatriptan benzoate, rmulation, rociletinib, roflumilast, rokitamycin,rolapitant, romurtide, ronacaleret, roneparstat, ronopterin, ropinirole,ropinirole hydrochloride, ropivacaine, rosebengal sodium, rosiglitazone,rosiglitazone maleate, rosiglitazone sodium, rostafuroxin, rosuvastatin,rosuvastatin calcium, rotigotine, rovatirelin, roxadustat,roxithromycin, rubitecan, rucaparib phosphate, rufinamide, rufloxacin,rupatadine, ruxolitinib, S-(−)-ornidazole phosphate disodium,sabarubicin, sacubitril, safinamide, salbutamol, salbutamol sulfate,salicyclic acid, salmeterol, salmeterol xinafoate, salubrinal,salvicine, samarium(153Sm) lexidronam, samidorphan, S-amlodipinenicotinate, sapacitabine, sapropterin, sapropterin dihydrochloride,saquinavir, saracatinib, sarecycline, saroglitazar, sarpogrelatehydrochloride, savolitinib, saxagliptin, scopolamine, scorpionvenom,omega-3polyunsaturated fatty acid, secnidazole, segesterone acetate,selegiline, selegiline hydrochloride, selepressin, selexipag,seliciclib, selinexor, selisistat, selumetinib, selurampanel,sepranolone, seratrodast, serlopitant, sertaconazole, sertaconazolenitrate, sertindole, sertraline, sertraline hydrochloride, setipiprant,sevelamer carbonate, sevelamer hydrochloride, seviteronel, sevoflurane,sevuparin sodium, sibutramine maleate, sibutramine mesylate, sildenafil,sildenafil citrate, silibinin dihydrogen succinate, silmitasertib,silodosin, silver sulfadiazine, simeprevir, simmitecan hydrochloride,simotinib hydrochloride, simvastatin, sinotecean, siponimod, sirolimus,sitafloxacin, sitagliptin, sitagliptinphosphate, sivelestat, sizofiran,smilagenin, S-modafinil, sobuzoxane, sodium aescinate, sodium ascorbate,sodium benzoate, sodium bicarbonate, sodium chromoglycate, sodiumferricgluconate complex, sodium glycididazole, sodium gualenate, sodiumhyaluronate, sodium ibandronate, sodium nitrate, sodium nitrite, sodiumoxybate, sodium phenylacetate, sodium phenylbutyrate, sodiumpolysulthionate, sodium prasteronesulfate, sodium pyruvate, sodiumtaurocholate, sodium thiosulfate, sodium zirconiumcyclosilicate,sofosbuvir, sofpironium bromide, solabegron, solifenacin, solithromycin,sonidegib, sonolisib, sophocarpine, sophoridine hydrochloride,sorafenib, sorbitol, sotagliflozin, sotirimod, sotrastaurin, sotylize,sovaprevir, sparfloxacin, sparsentan, spebrutinib, spirapril,spironolactone, squalamine, stannsoporfin, stavudine, S-tenatoprazole,stepronin, stiripentol, streptozocin, strontium malonate, strontiumranelate, succinic acid, sucralfate, sucroferric oxyhydroxide,sufentanil, suftalanzinc, sugammadex, sulbactam, sulbactam sodium,sulcardine sulfate, sulfamethoxypyrazine, sulfasalazine, sulfatinib,sulfonylurea, sulforaphane, sulfotanshinone sodium, sulindac,sulodexide, sulphamethoxazole, sulthiame, sumatriptan, sumatriptansuccinate, sunitinib, sunstone, suplasyn, suplatast tosilate, suraminsodium, verapamil hydrochloride, rilpivirine, sutezolid, suvorexant,tacalcitol, tacrine, tacrolimus, tadalafil, tafamidis, tafenoquine,tafluprost, tafoxiparin sodium, taladegib, talaporfin, talazoparib,talipexole, taltirelin, tamibarotene, tamoxifen, tamsulosin, tamsulosinhydrochloride, tandospirone, tanespimycin, tapentadol, tarafenacin,tarenflurbil, tarloxotinib bromide, taselisib, tasimelteon, tasquinimod,tavaborole, tavilermide, tazarotene, tazemetostat, tazobactam,tazobactam sodium, tebipenem pivoxil, tecarfarin, tecovirimat,tectorigenin sodiumsulfonate, tedisamil, tedizolid phosphate,tefinostat, tegafur, tegaserod, teicoplanin, telaprevir, telapristoneacetate, telatinib, telbivudine, telithromycin, telmisartan,telotristatetiprate, temanogrel, temocapril, temoporfin, temozolomide,temsirolimus, tenalisib, tenapanor, teneligliptin, tenofovir,tenofoviralafenamide, tenofovirdipivoxil fumarate, tenofovir disoproxilaspartate, tenofovir disoproxil fumarate, tenoxicam, tepotinib,teprenone, terameprocol, terazosin, terbinafine, terbinafinehydrochloride, terguride, teriflunomide, tesevatinib, tesofensine,testosterone, testosterone undecanoate, tetrabenazine, tetracaine,tetracaine hydrochloride, tetrahydrocannabidiol, tetrathiomolybdate,tetryzoline, tezacaftor, thalidomide, theliatinib, theophylline,therapeutic, thiazide, thienorphine hydrochloride, thiotepa, thrombin,thromboreductin, thyroxine, tiagabine, tianeptine, tibolone, ticagrelor,ticlopidine, tigecycline, tiludronatedi sodium, timolol, timololmaleate, tindamax, tinidazole, tinzaparin sodium, tioconazole,tiopronin, tiotropium bromide, tiotropium bromide monohydrate,tipelukast, tipepidine hibenzate, tipifarnib, tipiracil hydrochloride,tipranavir, tirapazamine, tirasemtiv, tirilazad, tirofiban, tirofibanhydrochloride, tivantinib, tivozanib, tizanidine, tobramycin,tocofersolan, tocoretinate, tofacitinib, tofogliflozin, tolcapone,tolimidone, tolperisone, tolterodine, tolterodine tartrate, tolvaptan,tonabersat, topiramate, topiroxostat, topotecan, topotecanhydrochloride, torasemide, toreforant, toremifene, tosedostat,tosufloxacin, totrombopag, tozadenant, trabectedin, trabodenoson,tradipitant, tramadol, tramadol hydrochloride, trametinib, trandolapril,tranexamic acid, tranilast, transcrocetinate-sodium, transepithelialriboflavin, trantinterol hydrochloride, travoprost, trazodone,trehalose, trelagliptin succinate, treosulfan, treprostinil,treprostinil diolamine, tretinoin, triamcinolone acetonide, triapine,triazolam, tribendimidine, trichlormethiazide, triciribine,triclabendazole, triclocarban, trientine hydrochloride, trifarotene,trifluridine, triflusal, triheptanoin, trilostane,trimebutine3-thiocarbamoyl-benzenesulfonate, trimebutine tosylate,trimegestone, trimethoprim, trimetrexate, trinitrate, tripotassiumdicitratobismuthate, trofinetide, tropicamide, tropisetron,trospiumchloride, trovafloxacin, troxipide, tucatinib, tulobuterol,tylerdipinehydrochloride, ubenimex, ubidecarenone, ubrogepant, udenafil,ulinastatin, ulipristal, ulixertinib, ulobetasol, umeclidinium,umeclidinium bromide, upamostat, uprosertib, uracil, urapidil,uridinetriacetate, uroacitides, ursodeoxycholic acid, ursolicacid,vaborbactam, vadadustat, valaciclovir, valaciclovir hydrochloride,valbenazine, valdecoxib, valganciclovir, valomaciclovir stearate,valproic acid, valrubicin, valsartan, valsartan trisodiumhemipentahydrate, vancomycin, vancomycin hydrochloride, vandetanib,vaniprevir, vanoxerine, vapendavir, vardenafil hydrochloride,varenicline, varithena, varlitinib, vatiquinone, vavelta, veliparib,velpatasvir, velusetrag, vemurafenib, venetoclax, venlafaxine,venlafaxine hydrochloride, vepoloxamer, verapamil, verapamilhydrochloride, verdinexor, veregen, vericiguat, verinurad, vernakalant,vernakalant hydrochloride, verosudil, verteporfin, verubecestat,verubulin, vesatolimod, vesnarinone, vibegron, vicagrel, vigabatrin,vilanterol, vilanterol trifenatate, vilaprisan, vilazodone,vildagliptin, vincristine sulfate, vinflunine, vinorelbine, vinpocetine,vintafolide, viralym-C, vismodegib, vistusertib, vitamin E nicotinicate,vizomitin, voglibose, volasertib, volixibat potassium ethanolatehydrate, vonoprazan fumarate, vorapaxar, voriconazole, vorinostat,vortioxetine, vortioxetine hydrobromide, vosaroxin, voxilaprevir,warfarin, xemilofiban, yimitasvir, yonkenafil, zabofloxacin,zafirlukast, zalcitabine, zaleplon, zaltoprofen, zamicastat, zanamivir,zemiStatin, Z-endoxifen hydrochloride, zibotentan, zidebactam,zidovudine, zileuton, zincacetate, zinostatin stimalamer, ziprasidone,zofenopril, zogenix, zoledronate D,L-lysinemonohydrate, zoledronatedisodium, zoledronic acid, zoliflodacin, zolmitriptan, zolpidem,zolpidem tartrate, zonisamide, zopiclone, zotepine, zucapsaicin,zuclopenthixol, and zuretinol acetate.

In certain embodiments, traditional Chinese medicine is selected fromthe group consisting of Abelmoschi Corolla, Abri Herba, Abutili Semen,Acanthopanacis Cortex Acanthopanacis Senticosi Radix Et Rhizoma SeuCaulis, Acanthopanax Extract, Achilleae Herba, Achyranthis BidentataeRadix, Aconiti Kusnezoffii Folium, Aconiti Kusnezoffii Radix Cocta,Aconiti Kusnezoffii Radix, Aconiti Lateralis Radix Praeparata, AconitiRadix Cocta, Aconiti Radix, Acori Calami Rhizoma, Acori TatarinowiiRhizoma, Adenophorae Radix, Aesculi Semen, Agkistrodon, AgrimoniaeHerba, Ailanthi Cortex, Ajugae Herba, Akebiae Caulis, Akebiae Fructus,Albiziae Cortex, Albiziae Flos, Alismatis Rhizoma, Allii MacrostemonisBulbus, Allii Sativi Bulbus, Allii Tuberosi Semen, Aloe, AlpiniaeKatsumadai Semen, Alpiniae Officinarum Rhizoma, Alpiniae OxyphyllaeFructus, Alumen, Amomi Fructus Rotundus, Amomi Fructus, AmpelopsisRadix, Andrographis Herba, Andrographolides, Anemarrhenae Rhizoma,Anemones Raddeanae Rhizoma, Angelicae Dahuricae Radix, AngelicaePubescentis Radix, Angelicae Sinensis Radix, Anisi Stellati Fructus,Apocyni Veneti Folium, Aquilariae Lignum Resinatum, Arcae Concha, ArctiiFructus, Ardisiae Crenatae Radix, Ardisiae Japonicae Herba, ArecaePericarpium, Arecae Semen Tostum, Arecae Semen, Arisaema Cum Bil,Arisaematis Rhizoma Preparatum, Arisaematis Rhizoma, AristolochiaeFructus, Aristolochiae Herba, Armeniacae Semen Amarum, Arnebiae Radix,Artemisiae Annuae Herba, Artemisiae Argyi Folium, Artemisiae ScopariaeHerba, Asari Radix Et Rhizoma, Asiatic Moonseed Root Extract, AsiniCorii Colla, Asparagi Radix, Aspongopus, Asteris Radix Et Rhizoma,Astragali Complanati Semen, Astragali Radix Praeparata Cum Melle,Astragali Radix, Atractylodis Macrocephalae Rhizoma, AtractylodisRhizoma, Aucklandiae Radix, Aurantii Fructus Immaturus, AurantiiFructus, Bambusae Caulis In Taenias, Bambusae Concretio Silicea,Baphicacanthis Cusiae Rhizoma Et Radix, Belamcandae Rhizoma, BelladonnaExtract, Belladonna Liquid Extract, Belladonnae Herba, BenincasaeExocarpium, Benzoinum, Berberidis Radix, Bergeniae Rhizoma, Bergenin,Bistortae Rhizoma, Bletillae Rhizoma, Bolbostemmatis Rhizoma, BombyxBatryticatus, Borneolum Syntheticum, Borneolum, Bovis CalculusArtifactus, Bovis Calculus Sativus, Bovis Calculus, Breviscapine,Broussonetiae Fructus, Bruceae Fructus, Bubali Cornu, Buddlejae Flos,Bufonis Venenum, Bungarus Parvus, Bupleuri Radix, Calamina, CallicarpaeCaulis Et Folium, Callicarpae Formosanae Folium, CallicarpaeMacrophyllae Folium, Calomelas, Campsis Flos, Canarii Fructus,Canavaliae Semen, Cannabis Fructus, Capsici Fructus, Carotae Fructus,Carpesii Fructus, Carthami Flos, Caryophylli Flos, Caryophylli Fructus,Cassiae Semen, Castor Oil, Catechu, Celosiae Cristatae Flos, CelosiaeSemen, Centella Total Glucosides, Centellae Herba, Centipedae Herba,Cera Chinensis, Cera Flava, Cervi Cornu Degelatinatum, Cervi CornuPantotrichum, Cervi Cornu, Cervi Cornus Colla, Chaenomelis Fructus,Changii Radix, Chebulae Fructus Immaturus, Chebulae Fructus, ChelidoniiHerba, Chinese Angelica Liquid Extract, Chloriti Lapis, ChoerospondiatisFructus, Chrysanthemi Flos, Chrysanthemi Indici Flos, ChuanxiongRhizoma, Cibotii Rhizoma, Cicadae Periostracum, Cichorii Herba, CichoriiRadix, Cimicifugae Rhizoma, Cinnabaris, Cinnamomi Cortex, CinnamomiRamulus, Cinnamon Oil, Cirsii Herba, Cirsii Japonici Herba Carbonisata,Cirsii Japonici Herba, Cissampelotis Herba, Cistanches Herba, CitriExocarpium Rubrum, Citri Fructus, Citri Grandis Exocarpium, CitriReticulatae Pericarpium Viride, Citri Reticulatae Pericarpium, CitriReticulatae Semen, Citri Sarcodactylis Fructus, Clematidis ArmandiiCaulis, Clematidis Radix Et Rhizoma, Clinopodii Herba, Cnidii Fructus,Codonopsis Radix, Coicis Semen, Commelinae Herba, Conyzae Herba,Coptidis Rhizoma, Cordyceps, Corni Fructus, Corydalis Bungeanae Herba,Corydalis Decumbentis Rhizoma, Corydalis Rhizoma, Crataegi Folium,Crataegi Fructus, Cremastrae Pseudobulbus, Pleiones Pseudobulbus, CrinisCarbonisatus, Croci Stigma, Crotonis Fructus, Crotonis Semen Pulveratum,Curculiginis Rhizoma, Curcumae Longae Rhizoma, Curcumae Radix, CurcumaeRhizoma, Cuscutae Semen, Cyathulae Radix, Cyclovirobuxine, CynanchiAtrati Radix Et Rhizoma, Cynanchi Paniculati Radix Et Rhizoma, CynanchiStauntonii Rhizoma Et Radix, Cynomorii Herba, Cyperi Rhizoma, DahurianRhododendron Leaf Oil, Dalbergiae Odoriferae Lignum, Daturae Flos,Dendrobii Caulis, Dendrobii Officinalis Caulis, DescurainiaeSemenlepidii Semen, Desmodii Styracifolii Herba, Dianthi Herba, DichroaeRadix, Dictamni Cortex, Dioscorea Panthaicae Rhizoma, DioscoreaeHypoglaucae Rhizoma, Dioscoreae Nipponicae Rhizoma, Dioscoreae Rhizoma,Dioscoreae Spongiosae Rhizoma, Dipsaci Radix, Draconis Sanguis,Drynariae Rhizoma, Dryopteridis Crassirhizomatis Rhizoma Carbonisatum,Dryopteridis Crassirhizomatis Rhizoma, Echinopsis Radix, Ecliptae Herba,Entadae Semen, Entianae Rhodanthae Herba, Ephedrae Herba, Ephedrae RadixEt Rhizoma, Epimedii Folium, Epimedii Wushanensis Folium, EquisetiHiemalis Herba, Erigerontis Herba, Eriobotryae Folium, Eriocauli Flos,Erodii Herba Geranii Herba, Erycibes Caulis, Eucalyptus Oil, EucommiaeCortex, Eucommiae Folium, Euodiae Fructus, Eupatorii Herba, EupatoriiLindleyani Herba, Euphorbiae Ebracteolatae Radix, Euphorbiae HirtaeHerba, Euphorbiae Humifusae Herba, Euphorbiae Pekinensis Radix,Euphorbiae Semen Pulveratum, Euphorbiae Semen, Eupolyphaga Steleophaga,Euryales Semen, Fagopyri Dibotryis Rhizoma, Farfarae Flos, FerulaeResina, Fibraureae Caulis, Fibriuretinin, Fluoritum, Foeniculi Fructus,Forsythiae Fructus, Fraxini Cortex, Fritillariae Cirrhosae Bulbus,Fritillariae Hupehensis Bulbus, Fritillariae Pallidiflorae Bulbus,Fritillariae Thunbergii Bulbus, Fritillariae Ussuriensis Bulbus,Galangae Fructus, Galla Chinensis, Galli Gigerii Endothelium Corneum,Ganoderma, Capillary Wormwood Extract, GardeniaeFructus Praeparatus,Gardeniae Fructus, Gastrodiae Rhizoma, Gecko, Gei Herba, GendarussaeHerba, Genkwa Flos, Gentianae Macrophyllae Radix, Gentianae Radix EtRhizoma, Ginger Liquid Extract, Ginkgo Folium, Ginkgo Leaves Extract,Ginkgo Semen, Ginseng Folium, Ginseng Radix Et Rhizoma Rubra, GinsengRadix Et Rhizoma, Glabrous Sarcandra Extract, Glechomae Herba,Gleditsiae Fructus Abnormalis, Gleditsiae Sinensis Fructus, GleditsiaeSpina, Glehniae Radix, Glycyrrhizae Radix Et Rhizoma Praeparata CumMelle, Glycyrrhizae Radix Et Rhizoma, Gossampini Flos, GranatiPericarpium, Gypsum Fibrosum, Gypsum Ustum, Haematitum, HaliotidisConcha, Halitum, Halloysitum Rubrum, Hawthorn Leave Extract, HedysariRadix Praeparata Cum Melle, Hedysari Radix, Hibisci Mutabilis Folium,Hippocampus, Hippophae Fructus, Hirudo, Homalomenae Rhizoma, HordeiFructus Germinatus, Houttuyniae Herba, Hydrargyri Oxydum Rubrum,Hyoscyami Semen, Hyperici Perforati Herba, Ilicis Chinensis Folium,Ilicis Cornutae Folium, Ilicis Rotundae Cortex, Ulicii Cortex,Impatientis Semen, Imperatae Rhizoma, Indigo Naturalis, Inulae Flos,Inulae Herba, Inulae Radix, Iridis Tectori Rhizoma, Isatidis Folium,Isatidis Radix, Juglandis Semen, Jujubae Fructus, Junci Medulla,Kadsurae Caulis, Kaempferiae Rhizoma, Kaki Calyx, Kansui Radix, KnoxiaeRadix, Kochiae Fructus, Lablab Semen Album, Laggerae Herba, LagotidisHerba, Laminariae Thallus Eckloniae Thallus, Lamiophlomis Herba,Lasiosphaera Calvatia, Leonuri Fructus, Leonuri Herba, Leonurus LiquidExtract, Licorice Extract, Licorice Liquid Extract, Ligustici Rhizoma EtRadix, Ligustri Lucidi Fructus, Lilii Bulbus, Limonitum, Linderae Radix,Lini Semen, Liquidambaris Fructus, Liquidambaris Resina, Liriopes Radix,Litchi Semen, Litseae Fructus, Lobeliae Chinensis Herba, Longan Arillus,Lonicerae Flos, Lonicerae Japonicae Caulis, Lonicerae Japonicae Flos,Lophatheri Herba, Luffae Fructus Retinervus, Lycii Cortex, LyciiFructus, Lycopi Herba, Lycopodii Herba, Lygodii Spora, LysimachiaeHerba, Lysionoti Herba, /-Borneolum, /-Menthol, Magnetitum, MagnoliaeFlos, Magnoliae Officinalis Cortex, Magnoliae Officinalis Flos, MahoniaeCaulis, Malvae Fructus, Manis Squama, Mantidis OOTheca, Margarita,Margaritifera Concha, Marsdeniae Tenacissimae Caulis, Mel, Melanteritum,Meliae Cortex, Melo Semen, Menispermi Rhizoma, Menthae HaplocalycisHerba, Meretricis Concha, Cyclinae Concha, Micae Lapis Aureus, MicroctisFolium, Mirabilitum Praeparatum, Momordicae Semen, Mori Cortex, MoriFolium, Mori Fructus, Mori Ramulus, Morindae Officinalis Radix, Moschus,Moslae Herba, Moutan Cortex, Mume Flos, Mume Fructus, Murrayae Folium EtCacumen, Mylabris, Myristicae Semen, Myrrha, Nardostachyos Radix EtRhizoma, Natrii Sulfas Exsiccatus, Natrii Sulfas, Nelumbinis Folium,Nelumbinis Plumula, Nelumbinis Receptaculum, Nelumbinis RhizomatisNodus, Nelumbinis Semen, Nelumbinis Stamen, Nigellae Semen, NotoginsengRadix Et Rhizoma, Notoginseng Total Saponins, Notoginseng TriolSaponins, Notopterygii Rhizoma Et Radix, Ocimum Gratissimum Oil,Olibanum, Omphalia, Ophicalcitum, Ophiopogonis Radix, OrostachyisFimbriatae Herba, Oroxyli Semen, Oryzae Fructus Germinatus, OsmundaeRhizoma, Ostreae Concha, Paeoniae Radix Alba, Paeoniae Radix Rubra,Panacis Japonici Rhizoma, Panacis Majoris Rhizoma, Panacis QuinquefoliiRadix, Papaveris Pericarpium SI, Paridis Rhizoma, Patchouli Oil,Pegaeophyti Radix Et Rhizoma, Peppermint Oil, Perillae Caulis, PerillaeFolium, Perillae Fructus, Periplocae Cortex, Persicae Ramulus, PersicaeSemen, Peucedani Decursivi Radix, Peucedani Radix, Pharbitidis Semen,Phellodendri Amurensis Cortex, Phellodendri Chinensis Cortex, Pheretima,Phragmitis Rhizoma, Phyllanthi Fructus, Physalis Calyx Seu Fructus,Physochlainae Radix, Phytolaccae Radix, Picrasmae Ramulus Et Folium,Picriae Herba, Picrorhizae Rhizoma, Pinelliae Rhizoma Praeparatum CumAlumine, Pinelliae Rhizoma Praeparatum Cum Zingibere Et Alumine,Pinelliae Rhizoma Praeparatum, Pinelliae Rhizoma, Pini Lignum Nodi, PiniPollen, Piperis Fructus, Piperis Kadsurae Caulis, Piperis Longi Fructus,Plantaginis Herba, Plantaginis Semen, Platycladi Cacumen, PlatycladiSemen, Platycodonis Radix, Pogostemonis Herba, Polygala Liquid Extract,Polygalae Japonicae Herba, Polygalae Radix, Polygonati Odorati Rhizoma,Polygonati Rhizoma, Polygoni Avicularis Herba, Polygoni CuspidatiRhizoma Et Radix, Polygoni Multiflori Caulis, Polygoni Multiflori RadixPraeparata, Polygoni Multiflori Radix, Polygoni Orientalis Fructus,Polygoni Perfoliati Herba, Polygoni Tinctorii Folium, Polyporus, Poria,Poriae Cutis, Portulacae Herba, Potentillae Chinensis Herba, PotentillaeDiscoloris Herba, Powerdered Buffalo Horn Extract, Prinsepiae Nux,Propolis, Prunellae Spica, Pruni Semen, Psammosilenes Radix,Pseudolaricis Cortex, Pseudostellariae Radix, Psoraleae Fructus,Pterocephali Herba, Puerariae Lobatae Radix, Puerariae Thomsonii Radix,Pulsatillae Radix, Pyritum, Pyrolae Herba, Pyrrosiae Folium, QuisqualisFructus, Rabdosiae Rubescentis Herba, Ranae Oviductus, Ranunculi TernatiRadix, Raphani Semen, Realgar, Rehmanniae Radix Praeparata, RehmanniaeRadix, Rhapontici Radix, Rhei Radix Et Rhizoma, Rhodiolae CrenulataeRadix Et Rhizoma, Rhododendri Daurici Folium, Rhododendri Mollis Flos,Rhubarb Extract, Rhubarb Liquid Extract, Ricini Semen, Rosae ChinensisFlos, Rosae Laevigatae Fructus, Rosae Rugosae Flos, Rubi Fructus, RubiaeRadix Et Rhizoma, Saigae Tataricae Cornu, Salvia Total Phenolic Acids,Salviae Miltiorrhizae Radix Et Rhizoma, Sanguisorbae Radix, Santali AlbiLignum, Saposhnikoviae Radix, Sappan Lignum, Sarcandrae Herba,Sargassum, Sargentodoxae Caulis, Sauropi Folium, Saururi Herba,Saussureae Involucratae Herba, Schisandrae Chinensis Fructus,Schisandrae Sphenantherae Fructus, Schizonepetae Herba Carbonisata,Schizonepetae Herba, Schizonepetae Spica Carbonisata, SchizonepetaeSpica, Scolopendra, Scorpio, Scrophulariae Radix, Scutellaria Extract,Scutellariae Barbatae Herba, Scutellariae Radix, Sedi Herba,Selaginellae Herba, Semiaquilegiae Radix, Senecionis Scandentis Hebra,Sennae Folium, Sepiae Endoconcha, Serpentis Periostracum, Sesame Oil,Sesami Semen Nigrum, Setariae Fructus Germinatus, Siegesbeckiae Herba,Silybi Fructus, Sinapis Semen, Sinomenii Caulis, Sinopodophylli Fructus,Siphonostegiae Herba, Siraitiae Fructus, Smilacis Chinae Rhizoma,Smilacis Glabrae Rhizoma, Sojae Semen Germinatum, Sojae Semen Nigrum,Sojae Semen Praeparatum, Solidaginis Herba, Sophorae Flavescentis Radix,Sophorae Flos, Sophorae Fructus, Sophorae Tonkinensis Radix Et Rhizoma,Sparganii Rhizoma, Spatholobi Caulis, Spiceleaf Kernel Oil, SpirodelaeHerba, Stachyuri Medulla Helwingiae Medulla, Stalactitum, Star AniseOil, Stauntoniae Caulis Et Folium, Stellariae Radix, Stemonae Radix,Stephaniae Tetrandrae Radix, Sterculiae Lychnophorae Semen, StrychniSemen Pulveratum, Strychni Semen, Styrax, Suis Fellis Pulvis, Sulfur,Swertiae Herba, Swertiae Mileensis Herba, Syngnathus, Syringae Cortex,Talci Pulvis, Talcum, Tamaricis Cacumen, Tanshinones, Taraxaci Herba,Taxilli Herba, Tea-Seed Oil, Terminaliae Belliricae Fructus, TestudinisCarapacis Et Plastri Colla, Testudinis Carapax Et Plastrum, TetrapanacisMedulla, Thlaspi Herba, Thunberg Fritillary Liquid Extract, TinosporaeRadix, Toatal Ginsenoside Of Ginseng Stems And Leaves, ToosendanFructus, Torreyae Semen, Total Ginsenoside Ginseng Root, ToxicodendriResina, Trachelospermi Caulis Et Folium, Trachycarpi Petiolus, TribuliFructus, Trichosanthis Fructus, Trichosanthis Pericarpium, TrichosanthisRadix, Trichosanthis Semen Tostum, Trichosanthis Semen, TrigonellaeSemen, Trionycis Carapax, Tsaoko Fructus, Turpentine Oil, TurpiniaeFolium, Typhae Pollen, Typhonii Rhizoma, Uncariae Ramulus Cum Uncis,Vaccariae Semen, Valerianae Jatamansi Rhizoma Et Radix, Verbenae Herba,Vespae Nidus, Vignae Semen, Violae Herba, Visci Herba, Vitex Oil,Viticis Fructus, Viticis Negundo Folium, Vladimiriae Radix, WeepingForsythia Extract, Wenyujin Rhizoma Concisum, Xanthii Fructus,Zanthoxyli Pericarpium, Zanthoxyli Radix, Zaocys, Zedoary Turmeric Oil,Zingiberis Rhizoma Praeparatum, Zingiberis Rhizoma Recens, ZingiberisRhizoma, Ziziphi Spinosae Semen.

In certain embodiments, the drug content further comprises a medium. Themedium can be associated with the API, i.e., the medium is in physicalcontact with the API. In certain embodiments, the API is embedded in themedium. In certain embodiments, the API is dispersed within the medium.In certain embodiments, the medium is made of a thermoplastic materialas disclosed herein.

In certain embodiments, the medium comprises a water-soluble excipientselected from the group consisting of cocoa butter, polyethylene glycol(PEG), sucrose, glucose, galactose, fructose, xyloselactose, maltose,trehalose, sorbitol, mannitol, maltodextrins, raffinose, stachyose,fructo-oligosaccharides and a combination thereof. In certainembodiments, the substrate further comprises a plasticizer.

The drug content can be of any suitable shape and size to be loaded intothe compartment.

In certain embodiments, the drug content is operably linked to thecompartment via covalent bond, non-covalent interactions or through alinker. Thus, the drug content and the substrate can be made separatelyand associate together through a covalent bond or non-covalentinteractions. In certain embodiments, dosage form is made by producingthe drug content and the substrate in a single process using 3D printingmethods.

In certain embodiments, the drug content is formed in the shape of acompressed tablet, an oval tablet, a pill, or a capsule. In certainembodiments, the shape of the drug content matches the shape of thecompartment. For example, when the compartment is a pie-shape, the drugcontent is also of a pie-shape, e.g., to fill the compartment.

In certain embodiments, the drug content is in the form of nanoparticlesas illustrated in FIG. 6. The drug content can be mixed with solution inwhich the API is either dissolved or suspended. The solution is thenatomized/sprayed atop a printing layer during the course of thethree-dimensional printing of the dosage form. Once the solutioncontaining the drug content dries, the drug content is dispersed in thedosage form. Nanoparticles have large surface area and will have highdissolution rate.

The size of the nanoparticles ranges from 1 nm to 900 nm in size(preferable 100-800 nm, 100-700 nm, 100-600 nm, 100-500 nm, 100-400 nm,100-300 nm, 100-200 nm, 1 nm, 2 nm, 3 nm, 4 nm, 5 nm, 6 nm, 7 nm, 8 nm,9 nm, 10 nm, 11 nm, 12 nm, 13 nm, 14 nm, 15 nm, 16 nm, 17 nm, 18 nm, 19nm, 20 nm, 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800nm, 900 nm in size). The size of nanoparticles can be controlled byselecting appropriate synthesis methods and/or systems. To obtainnanoparticles within a desired size range, the synthesis conditions maybe properly controlled or varied to provide for, e.g., a desiredsolution concentration or a desired cavity range (a detailed review canbe found at, e.g., Vincenzo Liveri, Controlled synthesis ofnanoparticles in microheterogeneous systems, Published by Springer,2006).

In certain embodiments, the drug content is in the form of microneedlesas illustrated in FIG. 7. The microneedle would be printed inconjunction with the dosage form or inserted into the dosage form duringthe three-dimensional printing of the dosage form. The microneedles canbe composed of a saccharide, a PLGA polymer or an API or a combinationthereof. The microneedle can assist in the penetration of an API intothe circulatory system of a patient when administered either parenteralor enteric.

In certain embodiments, the drug content forms a network. As shown inFIG. 8A, a dosage form has a substrate forming a compartment loaded witha drug content. The drug content has a substrate forming a network. Theframe structure of tablet is made of a material that dissolves between1-10 minutes, and the substrate dissolves in 2-60 seconds, preferably in2, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 seconds. As shown inFIG. 8B, the API can be released in seconds after the dosage form isadministered. In certain embodiments, the substrate also forms anetwork, which can further accelerate the release of the API.

The drug content can be made using an additive method such as fuseddeposition modeling (FDM). In certain embodiments, the drug content canbe made by using a three-dimensional printer (3D printer) configured toextruding a mixture of API and the excipient. The API can be melted andmixed homogenously with the melted substrate before being extruded.Alternatively, the API in a solid form (e.g., powder) can be mixed withand dispersed in the melted substrate before being extruded. In general,the extrusion process can be conducted at temperatures 10° to 40° C.above the glass transition (Tg) of the substrate and a temperature closeto the melting point of the API. Once at a suitable temperature for usein the three-dimensional printer, the substrate can be deposited to thethree-dimensional printing surface. The shape and size of the drugcontent can be controlled by programming the three-dimensional printingprocess. In certain embodiments, the drug content is fabricated in thesame process of the substrate. In certain embodiments, the drug contentis fabricated before the making of the substrate and loaded into thecompartment during or after the substrate is fabricated.

In certain embodiments, when the drug content is loaded into thecompartment, it is associated with the substrate, e.g., embedded orfixed in the substrate. In certain embodiments, the drug content isdetachable from the substrate when loaded into the compartment.

D. Controlled Release

The dosage form disclosed herein can offer various release profilesafter oral administration. In certain embodiments, the dosage formprovides a constant release profile, pulsatile or delayed delivery, ornon-linear drug release. In certain embodiments, the dosage formprovides a zero-order release kinetics.

A proper release profile may offer benefits to certain drug therapyregimes. For example, a pulsatile release profile offers controlledabsorption with resultant reduction in peak through ratios, targetedrelease of the drug to specific areas within the gastro intestinaltract, and absorption independent of the feeding state, thus may be usedto prevent tolerance, reduce the side-effects and improve patientcompliance, which is desirable to treat diseases like ADHD. For anotherexample, a release profile with a loading dose followed by a maintenancedose may be good for treating chronic conditions such as hypertensionand diabetes.

Some of the mechanisms to control the release profile using the dosagefrom disclosed herein have been discussed above. For example, bymanipulating the exposed surface area of the substrate that erodesconstantly over time, the drug content embedded in the substrate is ableto deliver a constant amount of drug over time. In addition, the releaseprofile can be controlled by the size of compartment opening and/or bythe geometric shape of the compartment.

In certain embodiments, the release profile can be controlled by thedesign of a compartment having an aperture that is sealed or blocked bya plug. The plug is made of a water-soluble, porous, or erodiblematerial or pH sensitive materials or hydrophobic material that willundergo attrition when the dosage form passing the GI tract. When thedosage form is administered to a subject, the plug is dissolved,permeated or eroded, thus releasing the drug content from thecompartment. The release profile of the drug content can be controlledby choosing a plug of proper erosion/dissolution rate or permeationrate. Alternatively, the release profile of the drug content can becontrolled by using the shape and/or the size of the plug (e.g., a rodshape of proper length). The release profile can also be controlled bythe number of the compartment. FIG. 9 shows an exemplary dosage formhaving a substrate forming a plurality of column-shaped compartmentsresiding on both sides of the dosage form. Each compartment is loadedwith a drug content. Each compartment has an aperture that is blocked bya rod-shaped plug. The plugs have different dissolution rate. Dependingon the size, shape and dissolution rate of the plug, the APIs can bereleased in a sustained, continuous, simultaneous, consecutive orpulsatile manner.

FIG. 10A shows an exemplary dosage form providing a consecutive releaseprofile. Referring FIG. 10A, the dosage form 700 has a substrate 701forming three column-shaped compartments 702˜704. Each compartment isloaded with a drug content of the same API. Each compartment has anaperture that is blocked by a rod-shaped plug 705˜707. The plugs aremade of the same material but have different length. Consequently, ittakes different amount of time to dissolve the plugs and to open thecompartments to release the drug content. As illustrated in FIG. 10C,the shortest plug dissolves first, releasing the API from the firstcompartment. When the API in the first compartment is completelyreleased, the plug of the median length dissolves, releasing the APIfrom the second compartment. When the API in the second compartment iscompletely released, the third plug dissolves to release the API fromthe third compartment. As a result, the plasma drug level reaches thefirst peak when the drug content in the first compartment is released.When the API released from the first compartment starts to beeliminated, the plasma drug level starts to decrease (see FIG. 10D).Before the plasma drug level falls below the critical level (thehorizontal line, below which the drug would be ineffective), the APIfrom the second compartment is released, and the plasma drug levelincreases again. When the API released from the second compartmentreaches the second peak and starts to be eliminated, the plug of thethird compartment dissolves to open the compartment. As a result, theplasma API level is maintained above the critical level for a long time,which benefits certain diseases.

The consecutive release manner can also be achieved through anotherexemplary dosage form having several drug contents packed in the form oflayers as illustrated in FIG. 10B. The API can be released in asustained manner by having each layer dissolving in synchrony to providea continuous, sustained release of API as depicted in FIG. 10C. Incertain embodiments, the outer layers of the dosage form dissolveimmediately and release the embedded drug content when the dosage formis administered. But the layers sandwiched in the middle do not dissolveor dissolve much slower because the outer layers block their interfacewith the environment. The dissolution of the outer layers exposes thelayers sandwiched in the middle and expedites their dissolution, thusproviding a consecutive release profile as illustrated in FIG. 10C.

In certain embodiments, the dosage form comprises a gas-generatingcomponent loaded into the first compartment. In certain embodiments, thegas-generating component is selected from the group consisting oforganic acid and carbonates, sulphites, bicarbonates, sodium carbonate,sodium bicarbonate, sodium metabisulphite, calcium carbonate, andcombinations thereof, which on contact with gastric fluid releasescarbon dioxide or sulphur dioxide gas. When the substrate is dissolved,permeated or eroded in stomach, the gas generating component is exposedto the acid environment or water penetrate into compartment to inducethe reaction between acid and sodium bicarbonate and generates gas torelease the drug content in an effervescent manner.

The dosage form disclosed herein may comprise one or more drug contentat least partially in delayed-release form, wherein the delayed releasemay be achieved with the assistance of conventional materials andmethods known to the person skilled in the art, for example by embeddingthe API in a delayed-release substrate/substrate or by the applicationof one or more delayed-release coatings. Through delayed release, APIrelease may be so controlled that twice or once daily administration ofthe dosage form is sufficient, which is advantageous in particular inthe case of a need for a sustained level active compound, e.g., forcombating pain.

In certain embodiments, the dosage form intends to release the activeingredients in oral cavity instantly. One example is to be given to oralcavity or take sublingual region.

In certain embodiments, the drug form can further comprise conventionalauxiliary substances known to the person skilled in the art, preferablyselected from the group consisting of glyceryl monostearate,semi-synthetic triglyceride derivatives, semi-synthetic glycerides,hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate,polyvinylpyrrolidone, gelatin, magnesium stearate, stearic acid, sodiumstearate, talcum, sodium benzoate, boric acid and colloidal silica,fatty acids, substituted triglycerides, glycerides, polyoxyalkyleneglycols and the derivatives thereof.

Manufacture of the Dosage Form

The controlled release dosage forms disclosed herein can be manufacturedusing any appropriate process. In certain embodiments, the dosage formsare produced using three-dimensional printing (3D printing).

As used herein, 3D printing refers to a process that produce 3D objectslayer-by-layer from digital designs. The basic process of 3D printinghas been described in U.S. Pat. Nos. 5,204,055; 5,260,009; 5,340,656;5,387,380; 5,503,785; and 5,633,021. Additional U.S. patents andapplications related to 3D printing include: U.S. Pat. Nos. 5,490,962;5,518,690; 5,869,170; 6,530,958; 6,280,771; 6,514,518; 6,471,992;8,828,411; U.S. PG Pub. Nos: 2002/0015728; 002/0106412; 2003/0143268;2003/0198677; 2004/0005360. Reference can be made to the patents andapplications listed above for a detailed description of 3D printing.

Different 3D printing methods have been developed for dosage formmanufacturing in terms of raw materials, equipment and solidification.These 3D printing methods include binder deposition (see L Gibson et al.(2015) Additive Manufacturing Technologies: 3D Printing, RapidPrototyping, and Direct Digital Manufacturing. 2 ed. Springer, New York;W. E. Katstra et al. (2000) Oral dosage forms fabricated by threedimensional printing, J. Control Release 66: 1-9; W. E. Katstra et al.(2001) Fabrication of complex oral delivery forms by three dimensionalprinting, Dissertation in Materials Science and Engineering,Massachusetts Institute of Technology; H. Lipson et al. (2013)Fabricated: The New World of 3D printing, John Wiley & Sons, Inc.; G.Jonathan, A. Karim (2016) 3D printing in pharmaceutics: a new tool fordesigning customized drug delivery systems, Int. J. Pharm. 499:376-394), material jetting (see G. Jonathan, A. Karim (2016) 3D printingin pharmaceutics: a new tool for designing customized drug deliverysystems, Int. J. Pharm. 499: 376-394), extrusion (see L Gibson et al.(2015) Additive Manufacturing Technologies: 3D Printing, RapidPrototyping, and Direct Digital Manufacturing. 2 ed. Springer, New York)and photopolymerization (see F. P. Melchels et al. (2010) A review onstereolithography and its application in biomedical engineering.Biomaterials 31: 6121-30).

In certain embodiments, the dosage forms disclosed herein aremanufactured using extrusion methods. In an extrusion process, materialis extruded from robotically-actuated nozzles. Unlike binder deposition,which requires a powder bed, extrusion methods can print on anysubstrate. A variety of materials can be extruded for 3D printing,including thermoplastic materials disclosed herein, pastes and colloidalsuspensions, silicones and other semisolids. One common type ofextrusion printing is fused deposition modeling, which uses solidpolymeric filaments for printing. In fused deposition modeling, a gearsystem drives the filament into a heated nozzle assembly for extrusion(see L Gibson et al. (2015) Additive Manufacturing Technologies: 3DPrinting, Rapid Prototyping, and Direct Digital Manufacturing. 2 ed.Springer, New York).

The manufacturing instructions for a print job may be generated avariety of ways, including direct coding, derivation from a solid CADmodel, or other means specific to the 3D printing machine's computerinterface and application software. These instructions may includeinformation on the number and spatial placement of droplets, and ongeneral print parameters such as the drop spacing in each lineardimension (X, Y, Z), and volume or mass of fluid per droplet. For agiven set of materials, these parameters may be adjusted in order torefine the quality of structure created. The overall resolution of thestructure created is a function of the powder particle size, the fluiddroplet size, the print parameters, and the material properties.

Because of its ability of handling a range of pharmaceutical materialsand control both composition and architecture locally, 3D printing iswell suited to the fabrication of dosage forms with complex geometry andcomposition in accordance with the present invention.

Manufacturing the dosage forms using 3D printing methods also facilitatepersonalized medicine. Personalized medicine refers to stratification ofpatient populations based on biomarkers to aid therapeutic decisions andpersonalized dosage form design. Modifying digital designs is easierthan modifying physical equipment. Also, automated, small-scale 3Dprinting may have negligible operating cost. Hence, 3D printing can makemultiple small, individualized batches economically feasible and enablepersonalized dosage forms designed to improve adherence.

Personalized dosage form allows for tailoring the amount of drugdelivered based on a patient's mass and metabolism. 3D printed dosageforms could ensure accurate dosing in growing children and permitpersonalized dosing of highly potent drugs. Personalized dosage formscan also combine all of patients' medications into a single daily dose,thus improve patients' adherence to medication.

FIG. 11 illustrates a process of using 3D printing to manufacturepersonalized dosage forms. For each patient, a variety of clinicaltesting results can be obtained, including body weight, age, metabolismindicator and genomic biomarkers, etc. The clinical testing results areinput into computer software. The information is combined with theprescription of physician and pharmaco-kinetic model to design a dosageform of specific dose and drug combination. The instruction is then sentto a 3D printer to manufacture the dosage form designed, which isadministered to the patient.

Controlled Release of Multiple Drugs

The dosage form and methods disclosed herein can be used to controlrelease of two or more drugs in order to optimize the drug combinationsin certain therapeutic regimes. For example, a tablet to treathypercholesterolemia can be designed to offer immediate release ofAtorvastatin calcium and extended release of nicotinic acid. In anotherexample, a non-steroidal anti-inflammatory drug (NSAID) for pain reliefmay be designed to provide sustained release of NSAID and a rapidrelease of H2-receptor antagonist for preventing NSAID-induced mucosaldamage.

In certain embodiments, the substrate forms multiple compartments, eachloaded with a drug content. In certain embodiments, the multiplecompartments are connected. In certain embodiments, the multiplecompartments are disconnected. In certain embodiments, the drug contentsloaded into different compartments are the same. In certain embodiments,the drug contents loaded into different compartments are different. Thedosage form can be so designed to provide simultaneous or sequentialrelease of multiple drug content to exert synergistic therapeuticeffects.

FIG. 12A shows an exemplary dosage form that can release APIssimultaneously. Referring to FIG. 12A, the dosage form 800 includesthree stacked layers 801˜803, each of which is embedded with a differentdrug content. As illustrated in FIG. 12B, when the dosage form 800 isadministered, the drug contents are released simultaneously but atdifferent rates as the layers dissolve.

FIG. 13A depicts another exemplary dosage form of simultaneous releaseprofile. Referring to FIG. 13A, the dosage form 900 includes threecolumn shaped compartments 901˜903, in which three drug contents areloaded. Each drug content contains an API embedded in a substrate ofdifferent dissolution rate. As illustrated in FIG. 13B, when the dosageform 900 is administered, the three APIs are released simultaneously butat different rates as the substrates of the drug contents dissolve. Therelease rate of the APIs can also be controlled by the shape of thecompartments or the size of the opening of the compartments.

FIGS. 14A and 14B depict additional exemplary dosage forms ofsimultaneous release profile of three APIs. Referring to FIG. 14A, thedosage form 1000 contains three pie-shaped segments 1001˜1003 whereindrug contents are embedded. As illustrated in FIG. 14C, the drugcontents release simultaneously as the segments dissolve, and therelease rate of the drug contents can be controlled by the dissolutionrate of the segments. Referring to FIG. 14B, the dosage form 1100contains three pie-shaped segments 1101˜1103, which are wrapped by ashell 1104 that dissolves slower than the segments. The release rates ofthe drug contents embedded in the segments are reduced as the shell 1104blocks the interface of the segments 1101˜1103 with the environment.

FIG. 15A shows an exemplary dosage form of sequential release profile oftwo APIs. Referring to FIG. 15A, the dosage form 1200 includes asubstrate 1201 forming a compartment that is filled by a drug content1202. The substrate 1201 contains a first API, and the drug content 1202contains a second API. As illustrated in FIG. 15B, the first APIreleases as the substrate dissolves when the dosage form isadministered. The second API does not release until the substratedissolves to expose the drug content, providing a sequential releaseprofiles of the APIs.

FIG. 16A shows another exemplary dosage form of sequential releaseprofiles. Referring to FIG. 16A, the dosage form 1300 has a substrate1301 forming three column-shaped compartments 1302˜1304 loaded withthree drug contents. The compartments 1302˜1304 have an aperture thatare blocked by rod-shaped plugs that have different length and/ordissolution rate. As illustrated in FIG. 16B, the APIs are released in asequential manner as the plugs dissolve sequentially to open thecompartments.

FIG. 17A shows an exemplary dosage form having a simultaneous releaseprofile or sequential release profile. Referring to FIG. 17A, the dosageform 1400 has a substrate containing four segments 1701˜1704 havingdifferent dissolution rate. In certain embodiments, as illustrated inFIG. 17B, the drug contents are embedded in the segments 1701˜1704 andare released simultaneously when the substrate dissolves. In certainembodiments, each segment contains a compartment where a drug content isloaded. As illustrated in FIG. 17C, the drug contents are released in asequential manner when the substrate dissolves.

Example 1

This example illustrates a design of dosage form that has controlledrelease profile.

As shown in FIG. 18A, the dosage form comprised a flat tablet substrateforming a pie shaped compartment. The substrate was made of PEG8000.Benzoic acid was used as a module drug content.

The release profile of the benzoic acid from the dosage form wasmeasured as the following method. Na₂HPO₄ solution of pH 8 was preparedas dissolvent of benzoic acid. Benzoic acid solution of 120 μg/mL wasserially diluted to 30 μg/mL, 15 μg/m, 7.5 μg/m, 3.75 μg/mL, and 1.875μg/mL solutions, whose absorbance at 226 nm was measured using a UVspectrophotometer. The numbers obtained were treated with linearregression to generate a standard curve of benzoic acid concentrationwith the formula y=0.0599x+0.0347. To measure the released amount ofbenzoic acid, the dosage form was dissolved in degassed pH 8 Na₂HPO₄solution at 37° C.±0.5° C. and centrifuged at 100 rpm. 5 mL solution wascollected from the solution at each time point to measure theconcentration of benzoic acid with 5 mL dissolvent added back to thesolution. The collected solution was filtered through 0.45 um membranebefore transferred to an UV spectrophotometer for measuring theabsorbance at 226 nm. The percentage of benzoic acid released wascalculated using the following formula:

${{Benzoic}\mspace{14mu}{acid}\mspace{14mu}{released}\mspace{14mu}(\%)} = {\frac{{C_{n}V_{t}} + {V_{s}\Sigma\; C_{n - 1}}}{Q_{{benzoic}\mspace{14mu}{acid}}} \times 100}$

-   -   Wherein    -   C_(n) means concentrate measured, V_(t) means total solution        volume, V_(s) means sample volume, Q_(benzoic acid) means amount        of benzoic acid in the dosage form

The release of PEG8000 is measured using the following method. Toprepare a standard curve of PEG8000, 0.1275 g PEG8000 standard samplewas dissolved in water in a 25 mL volumetric flask. Transferring 1 mL, 2mL 5 mL and 10 mL to 10 mL volumetric flask, respectively, and dilutedin water to prepare the control solution. Injecting 50 ul controlsolutions to a liquid chromatography (three Waters Ultrahydrogel™120/250/500 connected in series, flow speed at 0.5 ml/min, temperatureat 40° C., measured by a differential refraction detector). The areas ofthe volume were measured and used as y-axis. The log numbers of thecontrol solution concentration were used as x-axis. A standard curve ofPEG8000 was generated with the formula of y=1.024x+8.918. The percentageof PEG800 released was calculated using the following formula:

${{PEG}\; 8000\mspace{14mu}{released}\mspace{14mu}(\%)} = {\frac{{C_{n}V_{t}} + {V_{s}\Sigma\; C_{n - 1}}}{Q_{{PEG}\; 8000}} \times 100}$

-   -   wherein C_(n) means concentration measured,    -   V_(t) means volume of solution, V_(s) means sample volume,

Q_(PEG8000) means amount of PEG8000 in the dosage form

Results: as illustrated in FIG. 18C, the release profile of the benzoicacid matches a model profile according to D. Brooke and R. J. Washkuhn(Zero-Order Drug Delivery System: Theory and Preliminary Testing, JPharm Sci., 1977, 66: 159-162) and was controlled by the interface.Therefore, a controlled release profile can be designed according to thedosage forms disclosed herein.

Example 2

This example illustrates a design of dosage form that controls releaseof drug contents from different compartments.

Dosage design: two dosage forms were produced using fused depositionmodeling methods. The substrate of the dosage forms was made ofCopovidone (Kollidon® VA64) 72%, PEG1500 18% and Soluplus® 10%. The drugcontent was consisted of Moxifloxacin Hydrochloride 30%, PEG1000 70%.The schematic of the dosage forms are illustrated in FIGS. 19A and 19B.Referring to FIGS. 19A and 19B, the dosage form 1600 contained asubstrate 1601 that forms two compartments 1602 and 1603. Thecompartments were enclosed by a wall 1604 and 1605, respectively. Forthe first dosage form, the two compartments were enclosed by wallshaving a thickness of 0.75 mm and 1.5 mm, respectively. For the seconddosage form, the two compartments were enclosed by walls having athickness of 0.75 mm and 2.25 mm, respectively.

To detect the release of the drug content, the dosage form was added to900 ml phosphate buffer of pH6.8 at 100 rpm. The UV absorption of thebuffer was assayed to determine the release of the drug content.

The results of the release assays were illustrated in FIGS. 19C and 19D.As shown in FIG. 19C, when the first dosage form was added to the bufferfor 20 min, the first compartment was open, and the drug content in thefirst compartment was released. The second compartment was not open till40 min after the dosage form was added to the buffer. For the seconddosage form, whose results were illustrated in FIG. 19D, the secondcompartment was not open till 60 min after the dosage form was added tothe buffer. Therefore, the release profile of the dosage form can becontrolled through the thickness of the wall that encloses acompartment.

While the principles of this invention have been described in connectionwith specific embodiments, it should be understood clearly that thesedescriptions are made only by way of example and are not intended tolimit the scope of the invention. What has been disclosed herein hasbeen provided for the purposes of illustration and description. It isnot intended to be exhaustive or to limit what is disclosed to theprecise forms described. Many modifications and variations will beapparent to the practitioner skilled in the art. What is disclosed waschosen and described in order to best explain the principles andpractical application of the disclosed embodiments of the art described,thereby enabling others skilled in the art to understand the variousembodiments and various modifications that are suited to the particularuse contemplated. It is intended that the scope of what is disclosed bedefined by the following claims and their equivalence.

TABLE 1 Commercial Water Polymer Vendor Name Chemical StructureSolubility Polyvinyl caprolactam- polyvinyl acetate- polyethylene glycolgraft copolymer 57/30/13 BASF SE, Germany Soluplus

25 w/w % Amphiphilic Soluplus + 10% Plasticizer Kolliphor P 188

40 w/w % (freely soluble) Soluplus + 10% n/a poorly Plasticizer solubleKolliphor RH40 Soluplus + 10% Plasticizer PEG 1500

soluble Polyvinylpyrrolidone- International PVP/VA 40 w/w %co-vinyl-acetate Specialty (freely (PVP-VA) Products soluble) Inc.,Manchester, UK International Specialty Products Inc., Wayne, NJ, USAPlasdone S-630

40 w/w % (freely soluble) Polyvinylpyrrolidone- BASF SE, Kollidon VA 6440 w/w % polyvinyl acetate Germany (freely copolymer soluble) (PVP-VA)60/40 Polyvinylpyrrolidone- polyvinyl acetate copolymer BASF SE, GermanyKollidon VA 64 + 10% Plasticizer Kolliphor P 188

40 w/w % (freely soluble) (PVP-VA) 60/40 Polyvinylpyrrolidone- BASF SE,Kollidon VA 64 + n/a poorly polyvinyl acetate Germany 10% Plasticizersoluble copolymer Kolliphor RH40 (PVP-VA) 60/40 Polyvinylpyrrolidone-polyvinyl acetate BASF SE, Germany Kollidon VA 64 + 10% Plasticizer

soluble copolymer PEG 1500 (PVP-VA) 60/40 PolyvinylpyrrolidoneInternational Plasdone K-29/32 soluble (PVP) Specialty PVP K30 ProductsInc., Wayne, NJ, USA PVP polyvinyl- soluble pyrrolidone k30 PVPPolyvinyl- soluble pyrrolidone K25 (PVP K25) PVP PVP K25 + Plasticizerdibutyl sebacate (DBS)

soluble PVP PVP K25 + Plasticizer Triethyl citrate (TEC) Kollidon 12 PFPVP Kollidon 12 PF + 10% Plasticizer Kolliphor P 188

40 w/w % (freely soluble) PVP Kollidon 12 PF + n/a 40 w/w % 10%Plasticizer (freely Kolliphor RH40 soluble) PVP Kollidon 12 PF + 10%Plasticizer PEG 1500

poorly soluble PVP Kollidon 17 PF soluble PVP Kollidon 17 PF + 10%Plasticizer Kolliphor P 188

40 w/w % (freely soluble) PVP Kollidon 17 PF + n/a 40 w/w % 10%Plasticizer (freely Kolliphor RH40 soluble) PVP Kollidon 17 PF + 10%Plasticizer PEG 1500

poorly soluble Spray formulated mixture of polyvinyl acetate (PVAc) andpolyvinylpyrrolidone (PVP) 80/20 BASF SE, Germany Kollidon SR

0 (Because PVAc is lipophilic and water insoluble?) Spray formulatedmixture of polyvinyl acetate (PVAc) and polyvinylpyrrolidone BASF SE,Germany Kollidon SR + 10% Plasticizer Kolliphor P 188

40 w/w % (freely soluble) (PVP) 80/20 Spray formulated BASF SE, KollidonSR + n/a poorly mixture of polyvinyl Germany 10% Plasticizer solubleacetate (PVAc) and Kolliphor RH40 polyvinylpyrrolidone (PVP) 80/20 Sprayformulated mixture of polyvinyl BASF SE, Germany Kollidon SR + 10%Plasticizer

soluble acetate (PVAc) and PEG 1500 polyvinylpyrrolidone (PVP) 80/20Polyethylene glycol-polyvinyl alcohol graft copolymer 25/75 BASF SE,Germany Kollicoat IR

40 w/w % (freely soluble) Polyethylene glycol- polyvinyl alcohol graftcopolymer 25/75 BASF SE, Germany Kollicoat IR + 10% Plasicizer PEG 1500

soluble Kollicoat IR-polyvinyl alcohol 60/40 BASF SE, Germany KollicoatProtect

25 w/w % Kollicoat IR-polyvinyl alcohol 60/40 BASF SE, Germany KollicoatProtect + 10% Plasticizer

soluble PEG 1500 Polyvinyl Alcohol (PVA or PV- OH) DuPont Company,Wilmington, Delaware Elvanol ®

soluble USA Hydroxypropyl cellulose (HPC) Ashland Aqualon FunctionalIngredients, Wilmington, DE, USA Klucel EF

soluble Klucel ELF R = H or CH₂CH(OH)CH₃ Ethyl cellulose (EC) DowChemical, Midland, MI, US Ethocel ®

soluble Poly(ethylene oxide) (PEO) Sigma-Aldrich Ltd, Poole, Dorset, UKPolyox ® WSR

Soluble Poly(ethylene glycol) (PEG) Dow Chemical, Carbowax ®

Soluble Midland, MI, US Hyperbranched Polyesteramide Polymer Factory,Stockholm, Sweden Hybrane S1200

Soluble Hydroxypropyl Methylcellulose or Hypromellose (HMPC) DowChemical, Midland, MI, US Methocel ® E4M, K4M, K15M

Soluble Hydroxypropyl Methylcellulose or Hypromellose (HMPC) ColorconInc., Shanghai, China HPMC (2910 grade)

Soluble Hydroxypropyl Methylcellulose or Hypromellose (HMPC) SyntapharmGmbH, Mülheim- Ruhr, Germany Pharmacoat ® 603 and 615

Soluble Hydroxypropyl Methylcellulose or Hypromellose (HMPC) Shin-EtsuCo., Ltd., Niigata, Japan Pharmacoat ® 603 (2910 grade)

Soluble Carbomer Lubrizol Advanced Materials Inc., Cleveland, OH, USCarbopol ® 974P + Eudragit L- 100-55

Soluble Lactose Quest International, Hoffman Estates, IL, USA LactoseAnhydrate DT NF

soluble Microcrystalline cellulose (MCC) FMC, Philadelphia, PA, USAAvicel ® PH 101

soluble Dibasic calcium phosphate Penwest Pharma- ceuticals, Patterson,NY Emcompress ®

soluble Xanthan gum CP Kelco U.S. Inc., Chicago, IL, USA XANTURAL ® 180

soluble Poly(methyl acrylate-co- methyl methacrylate-co- methacrylicacid)7:3:1 Evonik R€ohm GmbH, Darmstadt, Germany Eudragit ® 4135F +Plasticizer PEG8000

Poly(methyl acrylate-co- methyl methacrylate-co- methacrylic acid) 7:3:1Evonik R€ohm GmbH, Darmstadt, Germany Eudragit ® 4155F (freeze driedEUDRAGIT ® FS 30 D)

soluble at pH >7 Poly(methacrylic acid-co- Evonik Eudragit ® Smethylmethacrylate) 1:2 Industries, Piscataway, New Jersey, USAPoly(methacrylic acid-co- methylmethacrylate) 1:2 Evonik Industries,Piscataway, New Jersey, USA Eudragit ® S + Plasticizer Triethyl citrate(TEC)

Poly(methacrylic acid-co- Evonik Eudragit ® S + methylmethacrylate) 1:2Industries, Plasticizer PEG Piscataway, 8000 New Jersey, USAPoly(methacrylic acid-co- Evonik Eudragit ® S + soluble atmethylmethacrylate) 1:2 Industries, Plasticizer pH >7 [36] Piscataway,methylparaben New Jersey, USA Poly(methacylic acid-co-ethyl acrylate)1:1 Evonik Degussa Piscataway, NJ Eudragit L- 100-55

Soluble at pH >5.5 Poly(methacylic acid-co- methyl methacrylate) 1:1Evonik Degussa Piscataway, NJ Eudragit L-100

Soluble at pH >6.0 Hydroxypropyl Methylcellulose Phthalate orHypromellose phthalate Shin-Etsu Co., Ltd., Niigata, Japan HP-55F

Soluble at pH >5.5

Hydroxypropyl Methylcellulose Acetate Succinate or Hypromellose AcetateSuccinate (HPMCAS) Shin-Etsu Co., Ltd., Niigata, Japan Shin-Etsu AqoatMF

Soluble at pH >6.0 Hydroxypropyl Shin-Etsu Co., Shin-Etsu Soluble atMethylcellulose Acetate Ltd., Niigata, Aqoat LF pH >5.5 Succinate orHypromellose Japan Acetate Succinate (HPMCAS) Poly(dimethylaminoethyl-Rohm Eudragit E Soluble at methacrylate-co- GmbH & Co., pH <5methacrylic esters) Darmstadt, Germany Hydroxypropyl Shin-Etsu Co.,Shin-Etsu Soluble at Methylcellulose Acetate Ltd., Niigata, Aqoat MFpH >6.0 Succinate or Hypromellose Japan Acetate Succinate (HPMCAS)Poly(lactide-co-glycolide) Birmingham Polymers, Inc., Birmingham, AL,USA PLGA

insoluble Elvax ® 40W: EV28

insoluble Elvax ® 40W: EV9

insoluble Evatane ®

insoluble Polyethylene (PE) Scientific Polymer PE1400

insoluble Products Inc., Ontario, NY Polycaprolactone (PCL) ScientificPolymer Products Inc., Ontario, NY —

insoluble Carnauba Wax Noda — n/a insoluble Wax Co., Japan GlycerylPalmitostearate Gattefosse, Precirol ® insoluble Cedex, France ATO 5Hydrogenated Castor & Abitec Sterotex ® K n/a insoluble Soybean OilCorporation, Janesville WI, USA Cellulose acetate butyrate (CAB) EastmanChemical Company, Kingsport, Tennessee, USA CAB 381-0.5

insoluble CAB FMC, Newark, DE, USA CAB 500-1

insoluble Poly(vinyl acetate) (PVAc) Scientific Polymer Products Inc.,Ontario, NY Sentry ® plus

insoluble Poly(ethyl acrylate- co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) Rohm GmbH & Co., Darmstadt,Germany Eudragit RS PO (1:2:0.1)

insoluble Poly(ethyl acrylate- co-methyl methacrylate-co-trimethylammonioethyl methacrylate chloride) Rohm GmbH & Co., Darmstadt,Germany Eudragit RL PO (1:2:0.2)

insoluble Poly(butyl methacrylate- co-(2- dimethylaminoethyl)methacrylate-co-methyl methacrylate) 1:2:1 Evonik Industries, Essen,Germany

Evonik EUDRAGIT ® Industries, E PO Piscataway, New Jersey, USA

What is claimed is:
 1. A method of preparing a table comprising aplurality of layers, wherein each layer comprises a substrate, andwherein the tablet comprises a drug in the form of nanoparticlesdisposed between at least two of the plurality of layers, the methodcomprises: a) printing a first layer by three-dimensional (3D) printing;b) atomizing or spraying atop of the first layer a solution comprisingthe drug to form a plurality of nanoparticles on top of the first layer;and c) printing a second layer by 3D printing.
 2. The method of claim 1,wherein the tablet comprises at least three layers, wherein the tabletcomprises a first and a second drug in the form of nanoparticlesdisposed between the at least three of the plurality of layers, andwherein the method comprises: a) printing a first layer by 3D printing;b) atomizing or spraying atop of the first layer a solution comprisingthe first drug to form a plurality of nanoparticles on top of the firstlayer; c) printing a second layer by 3D printing; d) atomizing orspraying atop of the second layer a solution comprising the second drugto form a plurality of nanoparticles on top of the second layer; and e)printing a third layer by 3D printing.
 3. The method of claim 2, whereinthe first drug and the second drug are different.
 4. The method of claim2, wherein the first drug and the second drug are the same.
 5. Themethod of claim 1, further comprising mixing the drug with the solutionin which the drug is either dissolved or suspended before step b). 6.The method of claim 1, further comprising drying the solution comprisingthe drug after atomizing or spraying the solution comprising the drugatop of the first layer.
 7. The method of claim 1, wherein the substrateis erodible.
 8. The method of claim 1, wherein the substrate comprises adrug embedded therein.
 9. The method of claim 8, wherein the drugembedded within the substrate of each layer is different.
 10. The methodof claim 8, wherein the drug embedded within the substrate of each layeris the same.
 11. The method of claim 1, wherein the substrate thicknessis different among each layer.
 12. The method of claim 1, wherein thesubstrate thickness is the same among each layer.
 13. The method ofclaim 1, wherein the size of the nanoparticles is from about 1 nm toabout 900 nm.
 14. The method of claim 1, wherein the size of thenanoparticles is from about 100 nm to about 500 nm.
 15. The method ofclaim 1, wherein the size of the nanoparticles is from about 100 nm toabout 200 nm.